Novel inhibitors of Hepatitis C virus NS3 protease

ABSTRACT

The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

This application is a divisional of U.S. application Ser. No.11/065,572, filed Feb. 24, 2005, and claims the benefit of U.S.Provisional Application, Ser. No. 60/548,251 filed Feb. 27, 2004.

FIELD OF THE INVENTION

The present invention relates to novel hepatitis C virus (“HCV”)protease inhibitors, pharmaceutical compositions containing one or moresuch inhibitors, methods of preparing such inhibitors and methods ofusing such inhibitors to treat hepatitis C and related disorders. Thisinvention additionally discloses novel compounds as inhibitors of theHCV NS3/NS4a serine protease.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus thathas been implicated as the major causative agent in non-A, non-Bhepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH)(see, International Patent Application Publication No. WO 89/04669 andEuropean Patent Application Publication No. EP 381 216). NANBH is to bedistinguished from other types of viral-induced liver disease, such ashepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus(HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well asfrom other forms of liver disease such as alcoholism and primary biliarcirrhosis.

Recently, an HCV protease necessary for polypeptide processing and viralreplication has been identified, cloned and expressed. (See, e.g. U.S.Pat. No. 5,712,145). This approximately 3000 amino acid polyproteincontains, from the amino terminus to the carboxy terminus, anucleocapsid protein (C), envelope proteins (E1 and E2) and severalnon-structural proteins (NS1, 2, 3, 4a, 5a and 5b). NS3 is anapproximately 68 kda protein, encoded by approximately 1893 nucleotidesof the HCV genome, and has two distinct domains: (a) a serine proteasedomain consisting of approximately 200 of the N-terminal amino acids;and (b) an RNA-dependent ATPase domain at the C-terminus of the protein.The NS3 protease is considered a member of the chymotrypsin familybecause of similarities in protein sequence, overall three-dimensionalstructure and mechanism of catalysis. Other chymotrypsin-like enzymesare elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA andPSA. The HCV NS3 serine protease is responsible for proteolysis of thepolypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a andNS5a/NS5b junctions and is thus responsible for generating four viralproteins during viral replication. This has made the HCV NS3 serineprotease an attractive target for antiviral chemotherapy. The inventivecompounds can inhibit such protease. They also can modulate theprocessing of hepatitis C virus (HCV) polypeptide.

It has been determined that the NS4a protein, an approximately 6 kdapolypeptide, is a co-factor for the serine protease activity of NS3.Autocleavage of the NS3/NS4a junction by the NS3/NS4a serine proteaseoccurs intramolecularly (i.e., cis) while the other cleavage sites areprocessed intermolecularly (trans).

Analysis of the natural cleavage sites for HCV protease revealed thepresence of cysteine at P1 and serine at P1′ and that these residues arestrictly conserved in the NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions.The NS3/NS4a junction contains a threonine at P1 and a serine at P1′.The Cys→Thr substitution at NS3/NS4a is postulated to account for therequirement of cis rather than trans processing at this junction. See,e.q., Pizzi et al. (1994) Proc. Natl. Acad. Sci (USA) 91:888-892, Faillaet al. (1996) Folding & Design 1:35-42. The NS3/NS4a cleavage site isalso more tolerant of mutagenesis than the other sites. See, eg.,Kollykhalov et al. (1994) J. Virol. 68:7525-7533. It has also been foundthat acidic residues in the region upstream of the cleavage site arerequired for efficient cleavage. See, eg Komoda et al. (1994) J. Virol.68:7351-7357.

Inhibitors of HCV protease that have been reported include antioxidants(see, International Patent Application Publication No. WO 98/14181),certain peptides and peptide analogs (see, International PatentApplication Publication No. WO 98/17679, Landro et al. (1997) Biochem.36:9340-9348, Ingallinella et al. (1998) Biochem. 37:8906-8914,Llinàs-Brunet et al. (1998) Bioorg. Med. Chem. Lett. 8:1713-1718),inhibitors based on the 70-amino acid polypeptide eglin c (Martin et al.(1998) Biochem. 37:11459-11468, inhibitors affinity selected from humanpancreatic secretory trypsin inhibitor (hPSTI-C3) and minibodyrepertoires (MBip) (Dimasi et al. (1997) J. Virol. 71:7461-7469),cV_(H)E2 (a “camelized” variable domain antibody fragment) (Martin etal.(1997) Protein Eng. 10:607-614), and α1-antichymotrypsin (ACT)(Elzouki et al.) (1997) J. Hepat. 27:42-28). A ribozyme designed toselectively destroy hepatitis C virus RNA has recently been disclosed(see, BioWorld Today 9(217): 4 (Nov. 10, 1998)).

Reference is also made to the PCT Publications, No. WO 98/17679,published Apr. 30, 1998 (Vertex Pharmaceuticals Incorporated); WO98/22496, published May 28, 1998 (F. Hoffmann-La Roche AG); and WO99/07734, published Feb. 18, 1999 (Boehringer Ingelheim Canada Ltd.).

HCV has been implicated in cirrhosis of the liver and in induction ofhepatocellular carcinoma. The prognosis for patients suffering from HCVinfection is currently poor. HCV infection is more difficult to treatthan other forms of hepatitis due to the lack of immunity or remissionassociated with HCV infection. Current data indicates a less than 50%survival rate at four years post cirrhosis diagnosis. Patients diagnosedwith localized resectable hepatocellular carcinoma have a five-yearsurvival rate of 10-30%, whereas those with localized unresectablehepatocellular carcinoma have a five-year survival rate of less than 1%.

Reference is made to WO 00/59929 (U.S. Pat. No. 6,608,027, Assignee:Boehringer Ingelheim (Canada) Ltd.; Published Oct. 12, 2000) whichdiscloses peptide derivatives of the formula:

Reference is made to A. Marchefti et al, Synlett, S1, 1000-1002 (1999)describing the synthesis of bicylic analogs of an inhibitor of HCV NS3protease. A compound disclosed therein has the formula:

Reference is also made to W. Han et al, Bioorganic & Medicinal Chem.Lett, (2000) 10, 711-713, which describes the preparation of certainα-ketoamides, α-ketoesters and α-diketones containing allyl and ethylfunctionalities.

Reference is also made to WO 00/09558 (Assignee: Boehringer IngelheimLimited; Published Feb. 24, 2000) which discloses peptide derivatives ofthe formula:

where the various elements are defined therein. An illustrative compoundof that series is:

Reference is also made to WO 00/09543 (Assignee: Boehringer IngelheimLimited; Published Feb. 24, 2000) which discloses peptide derivatives ofthe formula:

where the various elements are defined therein. An illustrative compoundof that series is:

Reference is also made to U.S. Pat. No. 6,608,027 (Boehringer Ingelheim,Canada) which discloses NS3 protease inhibitors of the type:

wherein the various moieties are defined therein.

Current therapies for hepatitis C include interferon-α (INF_(α)) andcombination therapy with ribavirin and interferon. See, e.g., Beremgueret al. (1998) Proc. Assoc. Am. Physicians 110(2):98-112. These therapiessuffer from a low sustained response rate and frequent side effects.See, e.g., Hoofnagle et al. (1997) N. Enql. J. Med. 336:347. Currently,no vaccine is available for HCV infection.

Reference is further made to WO 01/74768 (Assignee: VertexPharmaceuticals Inc) published Oct. 11, 2001, which discloses certaincompounds of the following general formula (R is defined therein) asNS3-serine protease inhibitors of Hepatitis C virus:

A specific compound disclosed in the afore-mentioned WO 01/74768 has thefollowing formula:

PCT Publications WO 01/77113; WO 01/081325; WO 02/08198; WO 02/08256; WO02/08187; WO 02/08244; WO 02/48172; WO 02/08251; and pending U.S. patentapplication, Ser. No. 10/052,386, filed Jan. 18, 2002, disclose varioustypes of peptides and/or other compounds as NS-3 serine proteaseinhibitors of hepatitis C virus. The disclosures of those applicationsare incorporated herein by reference thereto.

There is a need for new treatments and therapies for HCV infection.There is a need for compounds useful in the treatment or prevention oramelioration of one or more symptoms of hepatitis C.

There is a need for methods of treatment or prevention or ameliorationof one or more symptoms of hepatitis C.

There is a need for methods for modulating the activity of serineproteases, particularly the HCV NS3/NS4a serine protease, using thecompounds provided herein.

There is a need for methods of modulating the processing of the HCVpolypeptide using the compounds provided herein.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofinhibitors of the HCV protease, pharmaceutical compositions containingone or more of the compounds, methods of preparing pharmaceuticalformulations comprising one or more such compounds, and methods oftreatment or prevention of HCV or amelioration of one or more of thesymptoms of hepatitis C using one or more such compounds or one or moresuch formulations. Also provided are methods of modulating theinteraction of an HCV polypeptide with HCV protease. Among the compoundsprovided herein, compounds that inhibit HCV NS3/NS4a serine proteaseactivity are preferred. The present invention discloses compounds, orenantiomers, stereoisomers, rotamers, tautomers, diastereomers andracemates of said compounds, or a pharmaceutically acceptable salt,solvate or ester of said compounds, said compounds having the generalstructure having the general structure shown in structural Formula 1:

FORMULA I

wherein:

R¹ is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹ and R¹⁰ can be the sameor different, each being independently selected from the groupconsisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, heteroalkyl-,heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, andheteroarylalkyl;

A and M can be the same or different, each being independently selectedfrom R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected toeach other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C(R);

L is C(H), C(R), CH₂C(R), or C(R)CH₂;

R, R′, R², and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to eachother such that NRR′ forms a four to eight-membered heterocyclyl;

and Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, R¹⁵ and R¹⁶ are connected to eachother to form a four to eight-membered cycloalkyl, heteroaryl orheterocyclyl structure, and likewise, independently R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl;wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

The above-noted statement “A and M are connected to each other such thatthe moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl” can beillustrated in a non-limiting matter as follows. Thus, for example, inthe case where A and M are connected such that the moiety:

shown above in Formula I forms a six -membered cycloalkyl (cyclohexyl),Formula I can be depicted as:

One with ordinary skill in the art will appreciate that similardepictions for Formula I can be arrived at when A and M shown above inthe moiety:

are connected to form a three, four, seven or eight-membered cycloalkyl,a four to eight-membered heterocyclyl, a six to ten-membered aryl, or afive to ten-membered heteroaryl.

The statement above: “alternately, R¹⁵ and R¹⁶ are connected to eachother to form a four to eight-membered cycloalkyl, heteroaryl orheterocyclyl structure, and likewise, independently R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl” means the following possibilities: (i) that R¹⁵ and R¹⁶are connected to form a cyclic structure while R¹⁷ and R¹⁸ are not; and(ii) that R¹⁷ and R¹⁸ are connected to form a cyclic structure. The twopossibilities are irrespective of each other.

In the above-noted definitions of R, R′, R², and R³ preferred alkyl ismade of one to ten carbon atoms, preferred alkenyl or alkynyl is made oftwo to ten carbon atoms, preferred cycloalkyl is made of three to eightcarbon atoms, and preferred heteroalkyl, heteroaryl or heterocycloalkylhas one to six oxygen, nitrogen, sulfur, or phosphorus atoms.

The compounds represented by Formula I, by themselves or in combinationwith one or more other suitable agents disclosed herein, can be usefulfor treating diseases such as, for example, HCV, HIV, AIDS (AcquiredImmune Deficiency Syndrome), and related disorders, as well as formodulating the activity of hepatitis C virus (HCV) protease, preventingHCV, or ameliorating one or more symptoms of hepatitis C. Suchmodulation, treatment, prevention or amelioration can be done with theinventive compounds as well as with pharmaceutical compositions orformulations comprising such compounds. Without being limited to theory,it is believed that the HCV protease may be the NS3 or NS4a protease.The inventive compounds can inhibit such protease. They can alsomodulate the processing of hepatitis C virus (HCV) polypeptide.

DETAILED DESCRIPTION

In an embodiment, the present invention discloses compounds which arerepresented by structural Formula 1 or a pharmaceutically acceptablesalt, solvate or ester thereof, wherein the various moieties are asdefined above.

In another embodiment, R¹ is NR⁹R¹⁰, and R⁹ is H, R¹⁰ is H, or R¹⁴wherein R¹⁴ is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl orheteroaryl-alkyl.

In another embodiment, R¹⁴ is selected from the group consisting of:

In another embodiment, R² is selected from the group consisting of thefollowing moieties:

In another embodiment, R³ is selected from the group consisting of:

wherein R³¹ is OH or O-alkyl; and

R³² is H, C(O)CH₃, C(O)OtBu or C(O)N(H)tBu.In an additional embodiment, R³ is selected from the group consisting ofthe following moieties:

In another embodiment, Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, R¹⁵ and R¹⁶ are connected to eachother to form a four to eight-membered cycloalkyl, heteroaryl orheterocyclyl structure, and likewise, independently R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl;wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, is aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

In an additional embodiment, G is NH.In an additional embodiment, Y is selected from the group consisting of:

wherein Y³¹ is selected from the group consisting of:

Y³² is selected from the group consisting of:

and Y¹² is selected from the group consisting of H, CO₂H, CO₂Me, OMe, F,Cl, Br, NH₂, N(H)S(O₂)CH₃, N(H)C(O)CH₃, NO₂, NMe₂, S(O₂)NH₂, CF₃, Me,OH, OCF₃, and C(O)NH₂ and Y³³ is selected from the group consisting of:

In another embodiment, the moiety:

is selected from the following structures:

In an additional embodiment, the moiety:

is selected from the following structures:

In a still additional embodiment, the moiety:

is selected from the following structures:

In a further additional embodiment, R¹ is NHR¹⁴, where R¹⁴ is selectedfrom the group consisting of:

R² is selected from the group consisting of the following moieties:

R³ is selected from the group consisting of the following moieties:

Y is selected from the group consisting of:

wherein Y³¹ is selected from the group consisting of:

Y³² is selected from the group consisting of:

and Y¹² is selected from the group consisting of H, CO₂H, CO₂Me, OMe, F,Cl, Br, NH₂, N(H)S(O₂)CH₃, N(H)C(O)CH₃, NO₂, NMe₂, S(O₂)NH₂, CF₃, Me,OH, OCF₃, and C(O)NH₂ and Y³³ is selected from the group consisting of:

and the moiety:

In a still additional embodiment, the present invention disclosescompounds shown in Table 1, Table 2, Table 3, Table 4, Table 5 and Table6 later in this specification. Also shown in the Tables are thebiological activities of several inventive compounds (as Ki* values).The range of Ki* in Tables 1-6 is defined as follows: A: <75 nM(nanomolar); B: 76-250 nM; and C: >250 nM.

Yet another embodiment of the invention discloses compounds in Table 7:TABLE 7

In an additional embodiment, this invention discloses the followingcompounds:

A still additional embodiment discloses the compounds in Table 8: TABLE8

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, —N(alkyl)₂, carboxy and —C(O)O-alkyl.Non-limiting examples of suitable alkyl groups include methyl, ethyl,n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. The term “substituted alkenyl” means that the alkenyl groupmay be substituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and—S(alkyl). Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like, as well aspartially saturated species such as, for example, indanyl,tetrahydronaphthyl and the like.

“Halogen” or “halo” means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂—and —SO₂NY₁Y₂, wherein Y₁ andY₂ can be the same or different and are independently selected from thegroup consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1- naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “one or more” or “at least one”, when indicating the number ofsubstituents, compounds, combination agents and the like, refers to atleast one, and up to the maximum number of chemically and physicallypermissible, substituents, compounds, combination agents and the like,that are present or added, depending on the context. Such techniques andknowledge are well known within the skills of the concerned artisan.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “isolated” or “in isolated form” for a compound refers to thephysical state of said compound after being isolated from a syntheticprocess or natural source or combination thereof. The term “purified” or“in purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples and Tables herein is assumed to have thehydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, N.Y.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula 1, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula 1 or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress, both of which are incorporated herein by reference thereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the CDK(s) and thus producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula 1 can form salts which are also within thescope of this invention. Reference to a compound of Formula 1 herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula 1 contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula 1 may be formed, for example, by reacting a compound ofFormula 1 with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1 986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of Formula 1, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations. The use ofthe terms “salt”, “solvate” “prodrug” and the like, is intended toequally apply to the salt, solvate and prodrug of enantiomers,stereoisomers, rotamers, tautomers, positional isomers, racemates orprodrugs of the inventive compounds.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

It is to be understood that the utility of the compounds of Formula 1for the therapeutic applications discussed herein is applicable to eachcompound by itself or to the combination or combinations of one or morecompounds of Formula 1 as illustrated, for example, in the nextimmediate paragraph. The same understanding also applies topharmaceutical composition(s) comprising such compound or compounds andmethod(s) of treatment involving such compound or compounds.

The compounds according to the invention can have pharmacologicalproperties; in particular, the compounds of Formula 1 can be inhibitorsof HCV protease, each compound by itself or one or more compounds ofFormula 1 can be combined with one or more compounds selected fromwithin Formula 1. The compound(s) can be useful for treating diseasessuch as, for example, HCV, HIV, (AIDS, Acquired Immune DeficiencySyndrome), and related disorders, as well as for modulating the activityof hepatitis C virus (HCV) protease, preventing HCV, or ameliorating oneor more symptoms of hepatitis C.

The compounds of Formula 1 may be used for the manufacture of amedicament to treat disorders associated with the HCV protease, forexample, the method comprising bringing into intimate contact a compoundof Formula 1 a pharmaceutically acceptable carrier.

In another embodiment, this invention provides pharmaceuticalcompositions comprising the inventive compound or compounds as an activeingredient. The pharmaceutical compositions generally additionallycomprise at least one pharmaceutically acceptable carrier diluent,excipient or carrier (collectively referred to herein as carriermaterials). Because of their HCV inhibitory activity, suchpharmaceutical compositions possess utility in treating hepatitis C andrelated disorders.

In yet another embodiment, the present invention discloses methods forpreparing pharmaceutical compositions comprising the inventive compoundsas an active ingredient. In the pharmaceutical compositions and methodsof the present invention, the active ingredients will typically beadministered in admixture with suitable carrier materials suitablyselected with respect to the intended form of administration, i.e. oraltablets, capsules (either solid-filled, semi-solid filled or liquidfilled), powders for constitution, oral gels, elixirs, dispersiblegranules, syrups, suspensions, and the like, and consistent withconventional pharmaceutical practices. For example, for oraladministration in the form of tablets or capsules, the active drugcomponent may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier, such as lactose, starch, sucrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, talc,mannitol, ethyl alcohol (liquid forms) and the like. Moreover, whendesired or needed, suitable binders, lubricants, disintegrating agentsand coloring agents may also be incorporated in the mixture. Powders andtablets may be comprised of from about 5 to about 95 percent inventivecomposition.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starch, methylcellulose, guar gum and the like.

Sweetening and flavoring agents and preservatives may also be includedwhere appropriate. Some of the terms noted above, namely disintegrants,diluents, lubricants, binders and the like, are discussed in more detailbelow.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. HCV inhibitory activity and thelike. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and pacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of the invention may also be administered orally,intravenously, intranasally or subcutaneously.

The compounds of the invention may also comprise preparations which arein a unit dosage form. In such form, the preparation is subdivided intosuitably sized unit doses containing appropriate quantities of theactive components, e.g., an effective amount to achieve the desiredpurpose.

The quantity of the inventive active composition in a unit dose ofpreparation may be generally varied or adjusted from about 1.0 milligramto about 1,000 milligrams, preferably from about 1.0 to about 950milligrams, more preferably from about 1.0 to about 500 milligrams, andtypically from about 1 to about 250 milligrams, according to theparticular application. The actual dosage employed may be varieddepending upon the patient's age, sex, weight and severity of thecondition being treated. Such techniques are well known to those skilledin the art.

Generally, the human oral dosage form containing the active ingredientscan be administered 1 or 2 times per day. The amount and frequency ofthe administration will be regulated according to the judgment of theattending clinician. A generally recommended daily dosage regimen fororal administration may range from about 1.0 milligram to about 1,000milligrams per day, in single or divided doses.

Some useful terms are described below:

Capsule—refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch forholding or containing compositions comprising the active ingredients.Hard shell capsules are typically made of blends of relatively high gelstrength bone and pork skin gelatins. The capsule itself may containsmall amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet—refers to a compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction.

Oral gel—refers to the active ingredients dispersed or solubilized in ahydrophillic semi-solid matrix.

Powder for constitution refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Diluent—refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn, rice and potato; and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about10 to about 90% by weight of the total composition, preferably fromabout 25 to about 75%, more preferably from about 30 to about 60% byweight, even more preferably from about 12 to about 60%.

Disintegrant—refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

Binder—refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

Lubricant—refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.2 to about 5% by weight of thecomposition, preferably from about 0.5 to about 2%, more preferably fromabout 0.3 to about 1.5% by weight.

Glident—material that prevents caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

Coloring agents—excipients that provide coloration to the composition orthe dosage form. Such excipients can include food grade dyes and foodgrade dyes adsorbed onto a suitable adsorbent such as clay or aluminumoxide. The amount of the coloring agent can vary from about 0.1 to about5% by weight of the composition, preferably from about 0.1 to about 1%.

Bioavailability—refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control.

Conventional methods for preparing tablets are known. Such methodsinclude dry methods such as direct compression and compression ofgranulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

Another embodiment of the invention discloses the use of the inventivecompounds or pharmaceutical compositions disclosed above for treatmentof diseases such as, for example, hepatitis C and the like. The methodcomprises administering a therapeutically effective amount of theinventive compound or pharmaceutical composition to a patient havingsuch a disease or diseases and in need of such a treatment.

In yet another embodiment, the compounds of the invention may be usedfor the treatment of HCV in humans in monotherapy mode or in acombination therapy (e.g., dual combination, triple combination etc.)mode such as, for example, in combination with antiviral and/orimmunomodulatory agents. Examples of such antiviral and/orimmunomodulatory agents include Ribavirin (from Schering-PloughCorporation, Madison, N.J.) and Levovirin™ (from ICN Pharmaceuticals,Costa Mesa, Calif.), VP ₅₀₄₀₆™ (from Viropharma, Incorporated, Exton,Pa.), ISIS ₁₄₈₀₃™ (from ISIS Pharmaceuticals, Carlsbad, Calif.),Heptazyme™ (from Ribozyme Pharmaceuticals, Boulder, Colo.), VX ₄₉₇™(from Vertex Pharmaceuticals, Cambridge, Mass.), Thymosin™ (fromSciClone Pharmaceuticals, San Mateo, Calif.), Maxamine™ (MaximPharmaceuticals, San Diego, Calif.), mycophenolate mofetil (fromHoffman-LaRoche, Nutley, N.J.), interferon (such as, for example,interferon-alpha, PEG-interferon alpha conjugates) and the like.“PEG-interferon alpha conjugates” are interferon alpha moleculescovalently attached to a PEG molecule. Illustrative PEG-interferon alphaconjugates include interferon alpha-2a (Roferon™, from Hoffman La-Roche,Nutley, N.J.) in the form of pegylated interferon alpha-2a (e.g., assold under the trade name PegaSyS™), interferon alpha-2b (Intron™, fromSchering-Plough Corporation) in the form of pegylated interferonalpha-2b (e.g., as sold under the trade name PEG-Intron™), interferonalpha-2c (Berofor Alpha™, from Boehringer Ingelheim, Ingelheim, Germany)or consensus interferon as defined by determination of a consensussequence of naturally occurring interferon alphas (Infergen™, fromAmgen, Thousand Oaks, Calif.).

As stated earlier, the invention includes tautomers, rotamers,enantiomers and other stereoisomers of the inventive compounds also.Thus, as one skilled in the art appreciates, some of the inventivecompounds may exist in suitable isomeric forms. Such variations arecontemplated to be within the scope of the invention.

Another embodiment of the invention discloses a method of making thecompounds disclosed herein. The compounds may be prepared by severaltechniques known in the art. Illustrative procedures are outlined in thefollowing reaction schemes. The illustrations should not be construed tolimit the scope of the invention which is defined in the appendedclaims. Alternative mechanistic pathways and analogous structures willbe apparent to those skilled in the art.

It is to be understood that while the following illustrative schemesdescribe the preparation of a few representative inventive compounds,suitable substitution of any of both the natural and unnatural aminoacids will result in the formation of the desired compounds based onsuch substitution. Such variations are contemplated to be within thescope of the invention.

For the procedures described below, the following abbreviations areused:

-   THF: Tetrahydrofuran-   DMF: N,N-Dimethylformamide-   EtOAc: Ethyl acetate-   AcOH: Acetic acid-   HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one-   EDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   NMM: N-Methylmorpholine-   ADDP: 1,1′-(Azodicarbobyl)dipiperidine-   DEAD: Diethylazodicarboxylate-   MeOH: Methanol-   EtOH: Ethanol-   Et2O: Diethyl ether-   DMSO: Dimethylsulfoxide-   HOBt: N-Hydroxybenzotriazole-   PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate-   DCM: Dichloromethane-   DCC: 1,3-Dicyclohexylcarbodiimide-   TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy-   Phg: Phenylglycine-   Chg: Cyclohexylglycine-   Bn: Benzyl-   Bzl: Benzyl-   Et: Ethyl-   Ph: Phenyl-   iBoc: isobutoxycarbonyl-   iPr: isopropyl-   ^(t)Bu or Bu^(t): tert-Butyl-   Boc: tert-Butyloxycarbonyl-   Cbz: Benzyloxycarbonyl-   Cp: Cylcopentyldienyl-   Ts: p-toluenesulfonyl-   Me: Methyl-   HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   DMAP: 4-N,N-Dimethylaminopyridine-   BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate-   PCC: Pyridiniumchlorochromate-   KHMDS: Potassium Hexamethyldisilazide or Potassium    bis(trimethylsilylamide)-   NaHMDS: Sodium Hexamethyidisilazide or Sodium    bis(trimethylsilylamide)-   LiHMDS: Lithium Hexamethyldisilazide or Lithium    bis(trimethylsilylamide)-   10% Pd/C: 10% Palladium on carbon (by weight).-   TG: Thioglycerol    General Schemes for Preparation of Target Compounds

Compounds of the present invention were synthesized using the generalschemes (Methods A-E) described below.

Method A

Deprotection of the N-Boc functionality of 1.01 under acidic conditionsprovided the hydrochloride salt 1.02 which was subsequently coupled withN-Boc-tert-leucine under peptide coupling methodology to afford 1.03.N-Boc deprotection followed by treatment with appropriate isocyanategave the urea 1.05. Hydrolysis of the methyl ester provided the acid1.06. Peptide coupling of the acid 1.06 with the appropriate P₁-P′primary amide moiety afforded the hydroxyl amide 1.07. Oxidation(Moffaft oxidation or related process—see, T. T. Tidwell, Synthesis,1990, 857), or Dess-Martin Periodinane—J. Org. Chem., (1983) 48, 4155)resulted in the target compound 1.08.

Method B

Peptide coupling of the acid 1.06 with the appropriate P₁-P′ secondaryamide moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt orDess-Martin's) resulted in the target compound 1.10.

Method C

In another variation, peptide coupling of the N-Boc-P2-P₃-acid 1.17 withthe appropriate P₁-P′ amide moiety afforded the hydroxyl amide 1.11.Oxidation (Moffatt or Dess-Martin Periodinane) resulted in the ketoamide 1.12. Deprotection of the N-Boc functionality gave thehydrochloride salt 1.13. Treatment with a suitable isocyanate (orisocyanate equivalent) resulted in the target compound 1.14.

Method D

In yet another variation, the hydrochloride salt 1.13 was converted tothe 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenylchloroformate. Subsequent treatment with an amine (or aminehydrochloride salt) of choice provided the target compound 1.14.

Method E

In yet another variation, the dipeptide hydrochloride salt 1.03 wasconverted to the 4-nitrophenyl carbamate as described above. Treatmentwith an amine (or amine hydrochloride salt) of choice provided the ureaderivative 1.05. Hydrolysis and further elaboration as described inMethods A/B provided the target compounds 1.14.

Preparation of P1-P′ MoietiesPreparation of Intermediates 10.11 and 10.12Step 1.

A stirred solution of ketimine 10.01 (50 g, 187.1 mmol) under N₂ in dryTHF (400 mL) was cooled to −78° C. and treated with 1 M solution ofK-^(t)BuO (220 mL, 1.15 equiv.) in THF. The reaction mixture was warmedto 0° C. and stirred for 1 h and treated with bromomethyl cyclobutane(28 mL, 249 mmol). The reaction mixture was stirred at room temperaturefor 48 h and concentrated in vacuo. The residue was dissolved in Et₂O(300 mL) and treated with aq. HCl (2 M, 300 mL) The resulting solutionwas stirred at room temperature for 5 h and extracted with Et₂O (1 L).The aqueous layer was made basic to pH ˜12-14 with NaOH (50% aq.) andextracted with CH₂Cl₂ (3×300 mL). The combined organic layers were dried(MgSO₄), filtered, and concentrated to give the pure amine (10.02, 18 g)as a colorless oil.Step 2.

A solution of the amine 10.02 (18 g, 105.2 mmol) at 0° C. in CH₂Cl₂ (350mL) was treated with di-tert-butyldicarbonate (23 g, 105.4 mmol) andstirred at rt. for 12 h. After the completion of the reaction (TLC), thereaction mixture was concentrated in vacuo and the residue was dissolvedin THF/H₂O (200 ml, 1:1) and treated with LiOH.H₂O (6.5 g, 158.5 mmol)and stirred at room temperature for 3 h. The reaction mixture wasconcentrated and the basic aqueous layer was extracted with Et₂O. Theaqueous layer was acidified with conc. HCl to pH˜1-2 and extracted withCH₂Cl₂. The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo to yield 10.03 as a colorless viscous oil whichwas used for the next step without any further purification.Step 3.

A solution of the acid 10.03 (15.0 g, 62 mmol) in CH₂Cl₂ (250 mL) wastreated with BOP reagent (41.1 g, 93 mmol), N-methyl morpholine (27 mL),N,O-dimethyl hydroxylamine hydrochloride (9.07 g, 93 mmol) and stirredovernight at rt. The reaction mixture was diluted with 1 N aq. HCl (250mL), and the layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (3×300 ml). The combined organic layers were dried (MgSO₄),filtered and concentrated in vacuo and purified by chromatography (SiO₂,EtOAc/Hex 2:3) to yield the amide 10.04 (15.0 g) as a colorless solid.Step 4.

A solution of the amide 10.04 (15 g, 52.1 mmol) in dry THF (200 mL) wastreated dropwise with a solution of LiAlH₄ (1M, 93 mL, 93 mmol) at 0° C.The reaction mixture was stirred at room temperature for 1 h andcarefully quenched at 0° C. with a solution of KHSO₄ (10% aq.) andstirred for 0.5 h. The reaction mixture was diluted with aq. HCl (1 M,150 mL) and extracted with CH₂Cl₂ (3×200 mL), The combined organiclayers were washed with aq. HCl (1 M), saturated NaHCO₃, brine, anddried (MgSO₄). The mixture was filtered and concentrated in vacuo toyield 10.05 as a viscous colorless oil (14 g).Step 5:

A solution of the aldehyde 10.05 (14 g, 61.6 mmol) in CH₂Cl₂ (50 mL),was treated with Et₃N (10.73 mL, 74.4 mmol), and acetone cyanohydrin(10.86 g, 127.57 mmol) and stirred at room temperature for 24 hrs. Thereaction mixture was concentrated in vacuo and diluted with aq. HCl (1M, 200 mL) and extracted into CH₂Cl₂ (3×200 mL). The combined organiclayer were washed with H₂O, brine, dried (MgSO₄), filtered, concentratedin vacuo and purified by chromatography (SiO₂, EtOAc/Hex 1:4) to yield10.06 (10.3 g) as a colorless liquidStep 6.

Methanol saturated with HCl*, prepared by bubbling HCl gas through CH₃OH(700 ml) at 0° C., was treated with the cyanohydrin 10.06 and heated toreflux for 24 h. The reaction was concentrated in vacuo to yield 10.07,which was used in the next step without purification.* Alternatively 6M HCl prepared by addition of AcCl to dry methanol canalso be used.Step 7.

A solution of the amine hydrochloride 10.07 in CH₂Cl₂ (200 mL) wastreated with Et₃N (45.0 mL, 315 mmol) and Boc₂O (45.7 g, 209 mmol) at−78° C. The reaction mixture was then stirred at room temperatureovernight and diluted with HCl (2 M, 200 mL) and extracted into CH₂Cl₂.The combined organic layers were dried (MgSO₄) filtered, concentrated invacuo and purified by chromatography (EtOAc/Hex 1:4) to yield hydroxyester 10.08.Step 8.

A solution of methyl ester 10.08 (3 g, 10.5 mmol ) in THF/H₂O (1:1) wastreated with LiOH.H₂O (645 mg, 15.75 mmol) and stirred at rt. for 2 h.The reaction mixture was acidified with aq HCl (1 M, 15 mL) andconcentrated in vacuo. The residue was dried in vacuum to afford 10.09in quantitative yield.Step 9

A solution of the acid 10.09 (from above) in CH₂Cl₂ (50 mL) and DMF (25mL) was treated with NH₄Cl (2.94 g, 55.5 mmol), EDCl (3.15 g, 16.5mmol), HOOBt (2.69 g, 16.5 mmol), and NMM (4.4 g, 44 mmol). The reactionmixture was stirred at room temperature for 3 d. The solvents wereremoved under vacuo and the residue was diluted with aq. HCl (250 mL)and extracted with CH₂Cl₂. The combined organic layers were washed withaq. saturated NaHCO₃, dried (MgSO₄) filtered concentrated in vacuo toobtain 10.10, which was used as it was in the following steps.(Alternatively 10.10 can also be obtained directly by the reaction of10.06 (4.5 g, 17.7 mmol) with aq. H₂O₂ (10 mL), LiOH.H₂O (820 mg, 20.8mmol) at 0° C. in 50 mL of CH₃OH for 0.5 h.).Step 10.

A solution of 10.10 obtained in the previous step was dissolved in 4 NHCl in dioxane and stirred at rt. for 2 h. The reaction mixture wasconcentrated in vacuo to give the intermediate 10.11 as a solid, whichwas used without further purification.Step 11.

The required intermediate 10.12 was obtained from compound 10.09 usingessentially the procedures described above in Steps 9, 10 withappropriate reagents.

Preparation of Intermediate 11.01

Step 1

To a solution of 4-pentyn-1-ol, 11.02 (4.15 g; Aldrich) was addedDess-Martin Periodinane (30.25 g; Aldrich) and the resulting mixture wasstirred for 45 min. before the addition of(tert-Butoxycarbonylmethylene)triphenylphosphorane (26.75 g; Aldrich).The resulting dark reaction was stirred overnight, diluted with EtOAc),washed with aq. sodium sulfite. sat. aq. NaHCO3, water, brine and dried.The volatiles were removed under reduced pressure and the residue waspurified by silica gel column chromatography using 1% EtOAc in hexanesas eluent to give the desired compound, 11.03 (3.92 g). Some impurefractions were also obtained but set aside at this time.Step 2

Using the alkene 11.03 (1.9 g) in n-propanol (20 ml; Aldrich)), benzylcarbamate (4.95 g; Aldrich) in n-propanol (40 ml), NaOH (1.29 g) inwater (79 ml), tert-butyl hypochlorite (3.7 ml), (DHQ)2PHAL (0.423 g;Aldrich)) in n-propanol (37.5 ml), and potassium osmate:dehydrate(0.1544 g; Aldrich) and the procedure set forth in Angew. Chem. Int. Ed.Engl (1998), ; (23/24), pp. 2813-7. gave a crude product which waspurified by silica gel column chromatography using EtOAc:Hexanes (1:5)to give the desired amino alcohol 11.04 (1.37 g, 37%) as a white solid.Step 3

To the ester 11.04 (0.700 g) was added 4M HCl in dioxane (20 ml;Aldrich) and the resulting mixture was allowed to stand at roomtemperature overnight. The volatiles were removed under reduced pressureto give the acid 11.05 (0.621 g) as a white solid.Step 4

BOP reagent (3.65 g; Sigma) followed by triethylamine (3.45 ml) wereadded to a dichloromethane (20 ml) solution of the carboxylic acid 11.05(2.00 g) and allyl amine (0.616 ml) at room temperature and theresulting mixture was stirred overnight. The reaction mixture waspartitioned between EtOAc and 10% aq. HCl. The organic phase wasseparated, washed with sat. aq. sodium bicarbonate, water, dried(magnesium sulfate). The crude reaction product was purified by silicagel column chromatography using (EtOAc:Hexanes; 70:30) as eluent toprovide the desired amide 11.01 (1.73 g) as a viscous yellow oil.

Preparation of Intermediates 12.03 and 12.04

Step 1

Compound 12.01 was converted to the required material 12.02 usingessentially the procedures described for Intermediate 10.11, Steps 3-8.Step 2

Compound 12.02 was converted to the required intermediate 12.03 usingessentially the procedures described for Intermediate 10.11, Steps 9,10.Step 3

Compound 12.02 was converted to the required intermediate 12.03 usingessentially the procedures described for Intermediate 10.12, Step 11.

Preparation of Intermediate 13.01

Step 1

To a stirred solution of 1-nitrobutane, 13.02 (16.5 g, 0.16 mol) andglyoxylic acid in H₂O (28.1 g, 0.305 mol) and MeOH (122 mL) at 0° C.-5°C., was added dropwise triethylamine (93 mL, 0.667 mol) over 2 hrs. Thesolution was warmed to room temperature, stirred overnight andconcentrated to dryness to give an oil. The oil was then dissolved inH₂O and acidified to pH=1 with 10% HCl, followed by extraction withEtOAc. The combined organic solution was washed with brine, dried overNa₂SO₄, filtered and concentrated to dryness to give the product 13.03(28.1 g, 99% yield).Step 2

To a stirred solution of compound 13.03 (240 g, 1.35 mol) in acetic acid(1.25 L) was added 10% Pd/C (37 g). The resulting solution washydrogenated at 59 psi for 3 hrs and then at 60 psi overnight. Theacetic acid was then evaporated and azeotroped 3 times with toluene,then triturated with MeOH and ether. The solution was then filtered andazeotroped twice with toluene to afford 13.04 as an off white solid (131g, 0.891 mol, 66%).Step 3

To a stirred solution of the amino acid 13.04 (2.0 g, 13.6 mmol) indioxane (10 mL) and H₂O (5 mL) at 0° C., was added 1N NaOH solution (4.3mL, 14.0 mmol). The resulting solution was stirred for 10 minutes,followed by addition of di-t-butyldicarbonate (0.110 g, 14.0 mmol) andstirred at 0° C. for 15 minutes. The solution was then warmed to roomtemperature, stirred for 45 minutes and kept at refrigerator overnightand concentrated to dryness to give a crude material. To the solution ofthis crude material in EtOAc (100 mL) and ice, was added KHSO₄ (3.36 g)and H₂O (32 mL) and stirred for 4-6 minutes. The organic layer was thenseparated and the aqueous layer was extracted twice with EtOAc and thecombined organic layer was washed with water, brine, dried over Na₂SO₄,filtered and concentrated to dryness to give the product 13.05 as aclear gum (3.0 g, 89% yield).Step 4:

Compound 13.05 was converted to the required intermediate 13.01 usingessentially the procedures described for Intermediate 10.12, Step 11.

Preparation of Intermediate 14.01

Step 1

Compound 14.02 was converted to the required material 14.03 usingessentially the procedures described for Intermediate 13.01, Steps 1-3.Step 2

Compound 14.03 was converted to the required intermediate 14.01 usingessentially the procedures described for Intermediate 10.12, Step 11.

Preparation of Intermediate 15.01

Step 1

To a suspension of silver nitrite (9 g, 58.5 mmol) in diethyl ether (25mL) at 0° C. was added a solution of 4-iodo-1,1,1-trifluorobutane, 15.02(10 g, 42.0 mmol) in diethyl ether (25 mL) slowly through an additionfunnel (approx. 15 min). The resulting mixture was vigorously stirred at0° C. and warmed to rt. After 50 h, the solid material was filtered offthrough a celite pad. The resulting diethyl ether solution wasconcentrated in vacuo to give 15.03 as colorless oil, which was usedwithout further purification.Step 2

Compound 15.03 was converted to the required material 15.04 usingessentially the procedures described for Intermediate 13.01, Steps 1-3.Step 3

Compound 15.04 was converted to the required intermediate 15.01 usingessentially the procedures described for Intermediate 10.12, Step 11.Preparation of Intermediate 16.01

The acid 16.02 (Winkler, D.; Burger, K., Synthesis, 1996, 1419) isprocessed as described above (preparation of Intermediate 10.12) to givethe expected intermediate 16.01

PREPARATION OF P2/P3-P2 MOIETIES

Preparation of Intermediate 20.01

The amino ester 20.01 was prepared following the method of R. Zhang andJ. S. Madalengoitia (J. Org. Chem. 1999, 64, 330), with the exceptionthat the Boc group was cleaved by the reaction of the Boc-protectedamino acid with methanolic HCl. (Note: In a variation of the reportedsynthesis, the sulfonium ylide was replaced with the correspondingphosphonium ylide).

Preparation of Intermediate 20.04

Step 1

A solution of commercial amino acid Boc-Chg-OH, 20.02 (Senn chemicals,6.64 g, 24.1 mmol) and amine hydrochloride 20.01 (4.5 g, 22 mmol) inCH₂Cl₂ (100 mL) at 0° C. was treated with BOP reagent and stirred at rt.for 15 h. The reaction mixture was concentrated in vacuo, then it wasdiluted with aq. 1 M HCl and extracted into EtOAc (3×200 mL). Thecombined organic layers were washed with saturated NaHCO₃ (200 mL),dried (MgSO₄), filtered and concentrated in vacuo, and chromatographed(SiO₂, EtOAc/Hex 3:7) to obtain 20.03 (6.0 g) as a colorless solid.Step 2:

A solution of methyl ester 20.03 (4.0 g, 9.79 mmol) in THF/H₂O (1:1) wastreated with LiOH.H₂O (401 mg, 9.79 mmol) and stirred at rt. for 3 h.The reaction mixture was acidified with aq. HCl and concentrated invacuo to obtain the required intermediate, free acid 20.04.

Preparation of Intermediate 20.07

Step 1

A solution of Boc-tert-Leu 20.05 (Fluka, 5.0 g 21.6 mmol) in dryCH₂Cl₂/DMF (50 mL, 1:1) was cooled to 0° C. and treated with the aminesalt 20.01 (5.3 g, 25.7 mmol), NMM (6.5 g, 64.8 mmol) and BOP reagent(11.6 g, 25.7 mmol). The reaction was stirred at rt. for 24 h, dilutedwith aq. HCl (1 M) and extracted with CH₂Cl₂. The combined organiclayers were washed with HCl (aq, 1 M), saturated NaHCO₃, brine, dried(MgSO₄), filtered and concentrated in vacuo and purified bychromatography (SiO2, Acetone/Hexane 1:5) to yield 20.06 as a colorlesssolid.Step 2

A solution of methyl ester 20.06 (4.0 g, 10.46 mmol) was dissolved in 4MHCl in dioxane and stirred at rt. for 3 h. The reaction mixture wasconcentrated in vacuo to obtain the amine hydrochloride salt, 20.07which was used without purification.

Preparation of Intermediate 21.01:

Step 1:

To a stirred solution of N-Boc-3,4-dehydroproline 21.02 (5.0 g, 23.5mmol), di-tert-butyl dicarbonate (7.5 g, 34.4 mmol), and4-N,N-dimethylaminopyridine (0.40 g, 3.33 mmol) in acetonitrile (100 mL)at room temperature was added triethylamine (5.0 mL, 35.6 mmol). Theresulting solution was stirred at this temperature for 18 h before itwas concentrated in vacuo. The dark brown residue was purified by flashcolumn chromatography eluting with 10-25% EtOAc/hexane to give theproduct 21.03 as a pale yellow oil (5.29 g, 84%).Step 2:

To a stirred solution of the dehydroproline derivative 21.03 (10.1 g,37.4 mmol), benzyltriethylammonium chloride (1.60 g, 7.02 mmol) inchloroform (120 mL) at room temperature was added 50% aqueous sodiumhydroxide (120 g). After vigorously stirred at this temperature for 24h, the dark mixture was diluted with CH₂Cl₂ (200 mL) and diethyl ether(600 mL). After the layers were separated, the aqueous solution wasextracted with CH₂Cl₂/Et₂O (1:2, 3×600 mL). The organic solution wasdried (MgSO₄) and concentrated. The residue was purified by flash columnchromatography using 5-20% EtOAc/hexane to afford 9.34 g (71%) of 21.04as an off-white solid.Step 3:

The solution of 21.04 (9.34 g, 26.5 mmol) in CH₂Cl₂ (25 mL) and CF₃CO₂H(50 mL) was stirred at room temperature for 4.5 h before it wasconcentrated in vacuo to give a brown residue, 21.05 which was used inStep 4 without further purification.Step 4

Concentrated hydrochloric acid (4.5 mL) was added to a solution of theresidue 21.05 from Step 3 in methanol (70 mL) and the resulting mixturewas warmed to 65° C. in an oil bath. After 18 h, the mixture wasconcentrated in vacuo to give a brown oil 21.01, which was used furtherwithout purification.

Preparation of Intermediate 22.01

Step 1

Potassium bis(trimethylsilyl)amide (158 ml of a 0.5M solution intoluene; 79 mmol) was added to a stirred suspension ofcyclopropyltriphenylphosphonium bromide (33.12 g; 86.4 mmol) inanhydrous tetrahydrofuran (130 ml) and the resulting orange mixture wasstirred under an atmosphere of nitrogen at room temperature for a periodof 1 h., before the addition of the aldehyde 22.02 (9.68 g; 42.2 mmol)in THF (8 ml). The reaction was then refluxed under an atmosphere ofnitrogen for a period of 2 h. After cooling, methanol, diethyl ether andRochelles salt were added. The organic phase was separated, washed withbrine, dried and concentrated under reduced pressure. The crude reactionproduct was purified by silica gel column chromatography usingEtOAc-hexane (1:99) to EtOAc-hexane (5:95) to provide the alkene 22.03(8.47 g) as a yellow oil.Step 2

A solution of 1M HCl in MeOH/MeOAc was prepared by adding 14.2 ml ofacetyl chloride dropwise into cold methanol and diluting the resultingsolution to 200 ml at room temperature.

The carbamate 22.03 (9.49 g; 37.5 mmol) was dissolved in methanol (12ml) and added to 1M HCl in MeOH/MeOAc (1 50 ml) while cooled in an icebath. The resulting mixture was maintained at this temperature for 1 h.,then the ice bath was removed and stirring continued overnight at roomtemperature. The volatiles were removed under reduced pressure to yielda yellow oil which was used in the next step without purification.

The yellow oil was dissolved in a mixture of THF (30 ml) and MeOH (20ml) and treated with triethylamine (15 ml; 108 mmol) until the solutionwas pH=9-10. After placing in an ice bath, the mixture was treated withN-Boc-Gly-OSu (11.22 g; 41 mmol). The ice bath was withdrawn and thereaction stirred at room temp. for 1 h. The volatiles were removed underreduced pressure and the residue was purified by silica gel columnchromatography using methanol (1-3%) in dichloromethane providing thedesired amide 22.04 (9.09 g).Step 3

The alcohol 22.04 (9.09 g; 33.6 mmol) was dissolved in acetone (118.5ml) and treated with 2,2-dimethoxypropane (37.4 ml; 304 mmol) andBF₃:Et₂O (0.32 ml; 2.6 mmol) and the resulting mixture was stirred atroom temperature for a period of 5.5 h The reaction solution was treatedwith a few drops of triethylamine and the volatiles were removed underreduced pressure. The residue was purified by silica gel columnchromatography using 5-25% EtOAc in hexanes to provide the N,O-acetal22.05 (8.85 g).Step 4

The carbamate 22.05 (8.81 g; 28.4 mmol) was dissolved in acetonitrile(45 ml) and the solution was cooled to −40° C. under an atmosphere ofnitrogen. Pyridine (6.9 ml; 85.3 mmol) followed by nitrosiumtetrafluoroborate (6.63 g; 56.8 mmol) were added and the resultingreaction mixture maintained below 0° C. until TLC indicated that nostarting material remained (approx. 2.25 h.). Pyrrolidine (20 ml; 240mmol) was added and the cooling bath was withdrawn and stirring wascontinued at room temperature for 1 h. and then the volatiles wereremoved under reduced pressure. The residue was quickly passed through apad of silica gel to provide a yellow oil.

The yellow oil was dissolved in anhydrous benzene (220 ml) and palladiumacetate (0.317 g; 1.41 mmol) was added before heating the resultingmixture to reflux, under an atmosphere of nitrogen for a period of 1.5h. After cooling, the volatiles were removed under reduced pressure andthe dark residue was purified by silica gel column chromatography usingEtOAc-hexane (1:4) to provide the I) the trans-pyrrolidinone 22.06 (1.94g) followed by ii) the cis-pyrrolidinone 22.07 (1.97 g).Step 5

Freshly prepared 1M HCl in MeOAc/MeOH (10 ml; as described above) wasadded to the N,O-acetal 22.06 and stirred at room temperature for 1 h.The solvent was removed under reduced pressure and the residue waspurified by silica gel column chromatography using 0-4% MeOH indichloromethane as eluent to provide the desired alcohol 22.08 (1.42 g),a yellow oil.Step 6

To a solution of the lactam 22.08 (1.29 g; 8.44 mmol) in anhydroustetrahydrofuran (55 ml) was added lithium aluminum hydride (2.40 g; 63.2mmol) and the resulting mixture was refluxed for 8 h. After cooling,water, followed by 15% aq. NaOH were added and the resulting mixture wasfiltered through celite and the solid was washed thoroughly with THF andMeOH. The solvent was removed under reduced pressure and the residueredissolved in dichloromethane, dried and concentrated under reducedpressure to provide the pyrrolidine, used without purification.

Hunigs base (4.5 ml; 25.8 mmol) was added to a mixture ofN-Boc-L-tert-Leu-OH (1.76 g; 7.6 mmol), The crude pyrrolidine and HATU(2.89 g; 7.6 mmol) in anhydrous dichloromethane (50 ml) at −60° C.,under an atmosphere of nitrogen. The resulting reaction was allowed tocome to room temperature slowly, overnight. EtOAc was added and theyellow solution was washed with dil. aq. HCl, sat. aq. sodiumbicarbonate, water, brine. The organic layer was dried and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography using EtOAc:hexanes (1:3) to give the desired amide 22.09(2.00 g).Step 7

The alcohol 22.09 (2.00 g; 5.67 mmol) was dissolved in acetone (116 ml)and cooled in an ice bath for 10 min. This solution was then added to acooled Jones reagent (14.2 ml; approx 2 mmol/ml) and the resultingmixture was stirred at 5° C. for 0.5 h and the cooling bath was removed.The reaction was stirred for a further 2 h. at room temp., before addingto sodium sulfate (28.54 g), celite (15 g) in EtOAc (100 ml).Isopropanol (15 ml) was added after 1 min and then stirred for a further10 min. and filtered. The filtrate was concentrated under reducedpressure, providing a brown oil which was dissolved in EtOAc. Thissolution was washed with water, 3% aq. citric acid, brine, dried andconcentrated to provide the desired carboxylic acid 22.01 (1.64 g) as awhite solid.

Preparation of Intermediate 23.01

Step 1:

To the mixture of ester 23.02 (6.0 g) and molecular sieve (5.2 g) inanhydrous methylene chloride (35 mL) was added pyrrolidine (5.7 mL,66.36 mmoL). The resulting brown slurry was stirred at room temperatureunder N₂ for 24 h, filtered and washed with anhydrous CH₃CN. Thecombined filtrate was concentrated to yield the desired product, 23.03.Step 2:

To a solution of the product 23.03 from proceeding step in CH₃CN (35 mL)was added anhydrous K₂CO₃, methallyl chloride (2.77 g, 30.5 mmoL), Nal(1.07 g, 6.7 mmoL). The resulting slurry was stirred at ambienttemperature under N₂ for 24 h. 50 mL of ice-cold water was addedfollowed by 2N KHSO₄ solution until pH was 1. EtOAc (100 mL) was addedand the mixture was stirred for 0.75 h. Combined organic layer wascollected and washed with brine, dried over MgSO₄, and evaporated toyield the desired product, 23.04.Step 3:

The product 23.04 from the preceding step (2.7 g, 8.16 mmoL) wasdissolved in dioxane (20 mL) and treated with freshly prepared 1N LiOH(9 mL). The reaction mixture was stirred at ambient temperature under N₂for 20 h. The reaction mixture was taken in EtOAc and washed with H₂O.The combined aqueous phase was cooled to 0° C. and acidified to pH 1.65using 1N HCl. The turbid mixture was extracted with EtOAc (2×100 mL).Combined organic layer was washed with brine, dried over MgSO₄, andconcentrated to give the desired acid, 23.05 (3.40 g).Step 4:

To a suspension of NaBH(OAc)₃ (3.93 g, 18.5 mmoL) in CH₂Cl₂ (55 mL) wasadded a solution of product 23.05 from preceding step in anhydrousCH₂Cl₂ (20 mL) and acetic acid (2 mL). The slurry was stirred at ambienttemperature for 20 h . Ice cold water (100 mL) was added to the slurryand stirred for ½ hr. Organic layer was separated, filtered, dried andevaporated to yield the desired product, 23.06.Step 5:

To a solution of the product 23.06 from preceding step (1.9 g) in MeOH(40 mL) was treated with excess of CH₂N₂/Et₂O solution and stirred forovernight. The reaction mixture was concentrated to dryness to yield acrude residue. The residue was chromatographed on silica gel, elutingwith a gradient of EtOAc/hexane to afford 1.07 g of the pure desiredproduct, 23.07.Step 6:

To a solution of product 23.07 from preceding step (1.36 g) in anhydrousCH₂Cl₂ (40 mL) was treated with BF₃. Me₂O (0.7 mL). The reaction mixturewas stirred at ambient temperature for 20 h and quenched with sat.NaHCO₃ (30 mL) ad stirred for ½ hr. Organic layer was separated andcombined organic layer was washed with brine, dried over MgSO₄,concentrated to give crude residue. The residue was chromatographed onsilica gel eluting with a gradient of EtOAc/hexane to afford 0.88 g ofthe desired compound, 23.08.Step 7:

To a solution of the product 23.08 (0.92 g) from preceding step in MeOH(30 mL) was added 10% Pd/C (0.16 g) at room temperature and hydrogenatedat ambient temperature under 1 atm. Pressure. The reaction mixture wasstirred for 4 h and concentrated to dryness to yield the desiredcompound, 23.01.

PREPARATION OF P3 MOIETIES

Preparation of Intermediate 50.01

Step 1

To a solution of 50.02 (15 g) in MeOH (150 mL) was added conc HCl (3-4mL) and the mixture was refluxed for 16 h. The reaction mixture wascooled to room temperature and concentrated. The residue was taken indiethyl ether (250 mL) and washed with cold saturated sodium bicarbonatesolution, and brine. The organic layer was dried (Na₂SO₄) andconcentrated to afford the methyl ester 50.03 (12.98 g) which wascarried forward without further purification.Step 2

The methyl ester 50.03 from above was dissolved in methylene chloride(100 mL) and cooled to −78° C., under nitrogen atmosphere. DIBAL (1.0 Msolution in methylene chloride, 200 mL) was added dropwise over 2 hperiod. The reaction mixture was warmed to room temperature over 16 h.The reaction mixture was cooled to 0° C. and MeOH (5-8 mL) was addeddropwise. A solution of aqueous 10% sodium potassium tartarate (200 mL)was slowly added with stirring. Diluted with methylene chloride (100 mL)and separated the organic layer (along with some white precipitate). Theorganic layer was washed with 1 N HCl (250 mL), brine (200 mL), dried(Na₂SO₄) and concentrated to provide the alcohol 50.04 (11.00 g) as aclear oil.Step 3

The alcohol 50.04 from above was dissolved in methylene chloride (400mL) and cooled to 0° C. under nitrogen atmosphere. PCC (22.2 g) wasadded in portions and the reaction mixture was slowly warmed to roomtemperature over 16 h. The reaction mixture was diluted with diethylether (500 mL) and filtered through a pad of celite. The filtrate wasconcentrated and the residue was taken in diethyl ether (500 mL). Thiswas passed through a pad of silica gel and the filtrate was concentratedto provide the aldehyde 50.05 which was carried forward without furtherpurification.Step 4

The aldehyde 50.05 from above was converted to the desired material50.01 using essentially the method of Chakraborty et. al (Tetrahedron,1995, 51(33), 9179-90).

PREPARATION OF SPECIFIC EXAMPLES FROM TABLE 1 Example I Preparation ofCompound of Formula 4010

Part I: Preparation of intermediate 4010.06

To a −20° C. solution of Amine 4010.01 (10 g, 72 mmol) preparedfollowing the method of R. Zhang and J. S. Madalengoitia (J. Org. Chem.1999, 64, 330) in DCM (200 mL) was added HATU (1.05 equiv, 28.8 g),Boc-L-Tert Leucine (Aldrich Chemical Co., Milwaukee, Wis., 1.1 equiv,79.2 mmol, 18.3 g) and DIPEA (0.2 mol, 40 mL). Reaction was stirred for24 h then was diluted with EtOAc and washed with NaHCO3. Organic layerwas washed with citric acid then brine. Organic layer was dried overMgSO4, filtered and concentrated under vacuo. The residue 4010.03 (72mmol) was dissolved in Acetone (1.2 L) at 0° C. Then, 5 equiv of Jonesreagent (138 mL, 360 mmol,. prepared by dissolving 91 g of Chromiumtrioxide in 70 mL of conc, H2SO4 and diluted to 300 mL) were added.After 45 min, no starting material was detected by TLC. Isopropanol (40mL) was added and 500 mL of EtOAc. The green solution was filtered offthrough a pad of celite and the filtrate concentrated to dryness. Theresidue was diluted with 10% sodium carbonate and extracted with Et₂O.The aqueous layer was then acidified to pH=2 with HCl 3.0 N andextracted with EtOAc (3 times 200 mL). Organic layer was dried overMgSO4, filtered and concentrated under vacuo. to yield 21.55 g ofintermediate 4010.04.Step2:

To a −20° C. solution 4010.04 (10.4 g, 28 mmol) in DCM (300 mL) wasadded HATU (1.05 equiv, 29.4 mmol, 11.2 g), amine salt 12.03 (1.0 equiv,28 mmol, 5.48 g, prepared as described in Preparation of intermediates,preparation of P1-P′ moieties). After 10 min at −20° C., DIPEA (3.6equiv, 100 mmol, 17.4 mL) was added. Reaction was stirred at this tempfor 16 h. After 16, the reaction was diluted with EtOAc and washedsuccessively with NaHCO3, citric acid (10% w/w) and brine. Organic layerwas dried over MgSO4, filtered and concentrated under vacuo. to yield:14 g of intermediate 4010.05.Step3:

Et3N (3 equiv., 5.2 mmol, 0.72 mL) is added to a mixture of crude4010.05 (1.06 g, 1.73 mmol theoretical) and EDCl (4 equiv., 6.92 mmol,1.33 g) in EtOAc (12 mL) at RT. After addition, DMSO (4.5 mL) was slowlycharged. This was followed by addition of methanesulfonic acid (3.6equiv, 6.22 mmol, 0.4 mL) with temperature between 20 and 30° C. Thereaction was agitated for 1 h. After 1 h, TLC shows reaction completed.At 0° C., a chilled mixture of EtOAc (12 mL) and iced water (2 mL) wasadded. After 2 minutes, the biphasic mixture was allowed to settle andthe layers were separated. The upper organic layer was washed with H2Oand brine. Organic layer was dried over MgSO4, filtered and concentratedunder vacuo. The residue was purified by HPFC, 25+M, 15% to 60% (EtOAc)in Hexanes. Purification provided (0.6 g) of ketoamide. To a RT solutionketoamide (0.6 g) was added 25 mL of a 4.0 N HCl solution in Dioxane.Reaction was stirred at RT for 1 h to observe completion thenconcentrated to about 5 mL and diluted with Heptanes and Ether.(10 mLeach). The resulting white precipitate was filtered off and dried undera N2 flow to provide 0.49 g (81% yield) of intermediate 4010.06.Part II: Preparation of intermediate 4010.10

Step 1:

PhMgBr (2.5 equiv, 40 mL) was added @ −78° C. to a Et2O (200 mL)solution of commercially available Weinreb amide 4010.07 (AldrichChemical Co., Milwaukee, Wis., USA, 12 g, 46 mmol). After 2 h, reactionwas quenched by addition of HCl 1.0 N, diluted with EtOAc and washedwith brine, dried over MgSO4, filtered and concentrated under vacuo. Theresidue was purified by HPFC Biotage 75+S, 2% (EtOAc) to 8% (EtOAc) inHexane. 3.76 g of 4010.08 were obtained.Step2:

To 4010.08 (1.93 g, 6.9 mmol) was added 5 mL of 4M HCl (in Dioxane). Thereaction was stirred at RT for 50 min and concentrated to dryness to get1.29 g of product 4010.09.Step3:

To a 0° C. solution of phosgene (6.3 mL) in CH₂Cl₂ (50 mL) and NaHCO₃(sat.) (50 mL) was added 4010.09 (1.29 g, 6 mmol). The mixture wasstirred at RT for 2.5 h then separated. Organic layer was dried overNa₂SO₄ (anhydrous) and concentrated under vacuum to half volume withcooling bath. Diluted it to 20 mL with CH₂Cl₂ to get 4010.10 as a 0.3Msolution in CH₂Cl₂.Part III: Preparation of Compound of Formula 4010 of Table 1

Following general method C: To a 0° C. solution of amine 4010.06 (20 mg,0.045 mmol) in CH2Cl2 (2 mL) was added isocyanate 4010.10 (2 equiv., 0.3mL) then DIPEA (0.035 mmol, 0.06 mL). The reaction was stirred at RT for1.2 hrs then diluted with EtOAc and washed with sat. NH4Cl and Brine.Organic layer was dried over MgSO4, filtered and concentrated todryness. Residue was purified by plate with 40% acetone in hexane to get12.7mg of product 4010 (46% yield); LCMS: (610.1: M+1), (632: M+Na).

HCV inhibitors 4028, 4031, 4062, 4082, 4102, 4109, 4110, 4119, 4120,4151, 4152, 4153, 4154, 4163, 4165, 4176, 4184 and 4201 described inTable 1 were prepared using intermediate 4010.10.

Example II Preparation of Intermediate of Formula 4035.01, 4044.01,4048.01, 4052.01, 4055.01, and 4076.01

Isocyanates 4035.01, 4044.01, 4055.01, 4048.01 and 4076.01 were preparedaccording the procedure outlined in preparative example I by replacingin step1 the commercially available (L)-Valine N,O-Dimethylhydroxylamide with the corresponding tert-Leucine, cyclohexylglycine,spirocyclohexylglycine, cyclobutylglycine, homovaline,cyclopentylglycine respectively. N,O-Dimethylhydroxyl amide wereprepared from commercially N-Boc amino acids following the procedureoutlined in step1 of preparative example of compound of formula 4032.

HCV inhibitors 4035, 4042, 4044, 4048, 4051, 4052, 4055, 4076, 4126,4141 and 4147 described in Table 1 were prepared using intermediates4005.01, 4035.01, 4048.01, 4052.01, 4055.01, and 4076.01 according tothe general procedures described before.

Example III Preparation of Intermediate of Formula 4011.01, 4079.01 and4097.01

Isocyanates 4011.01, 4079.01 and 4097.01 were prepared according theprocedure outlined in preparative example I by replacing in step1 thePhenylmagnesium bromide by the commercially available Benzylmagnesiumchloride and Phenethylmagnesium chloride with (L)-ValineN,O-Dimethylhydroxyl amide or (L)-Homovaline N,O-Dimethylhydroxyl amideor tert-Leucine N,O-Dimethylhydroxyl amide.

HCV inhibitors 4011, 4068, 4079 and 4097 described in Table 1 wereprepared using intermediates 4011.01, 4079,01 and 4097.01 according tothe general procedures described before.

Example IV Preparation of Intermediates of Formula 4012.01

X=F, Cl, Br, CF₃, OMe, OPh, OCH₂Ph, Me, NMe₂, SMe ortho, meta and parapositionR=(L)-Valine, (L)-tert-Leucine, (L)-Cyclhohexylglycine

Isocyanates of type 4012.01 were prepared according the procedureoutlined in preparative example I by replacing in step1 thePhenylmagnesium bromide by the corresponding commercially availableortho, meta or para-substituted Phenyl Grignard reagents (as an examplebut not limited to: X=F, Cl, Br, CF3, OMe, OPh, OCH₂Ph, Me, NMe₂, SMe)with (L)-Valine N,O-Dimethylhydroxyl amide or with the correspondingtert-Leucine and cyclohexylglycine N,O-Dimethylhydroxyl amide. HCVinhibitors 4012, 4027, 4029, 4045, 4064, 4071, 4075, 4083, 4088, 4090,4094, 4100, 4104, 4113, 4121, 4122, 4130, 4136, 4140, 4157, 4160 and4177 described in Table 1 were prepared using intermediates 4012.01according to the general procedures described before.

Example V Preparation of Intermediate of Formula 4017.01, 4078.01,4095.01, 4041.01, 4175.01 and 4190.01

Amine salts 4017.01, 4041.01, 4078.01, 4095.01 and 4175.01 were preparedaccording the procedure outlined in preparative example I step1 andstep2 by replacing in step1 the Phenylmagnesium bromide by thecorresponding Magnesium bromide Pyridine that were reacted with thecorresponding (L)-Valine N,O-Dimethylhydroxyl amide or (L)-HomovalineN,O-Dimethylhydroxyl amide or (L)-tert-Leucine N,O-Dimethylhydroxylamide or (L)-Cyclohexylglycine N,O-Dimethylhydroxyl amide. Thecorresponding 2, 3 and 4 Magnesium bromide Pyridine were preparedaccording Queguiner and all, Tetrahedron, 2000, 56, 1349-1360. For theamine salt 4190.01, 2 magnesium bromide pyridine was reacted withaldehyde 4190.02 and alcohol 4190.03 was oxidized to pyridine ketone4190.04 according scheme 4190.01.

HCV inhibitors 4017, 4022, 4041, 4065, 4078, 4095, 4096, 4101, 4168,4170, 4172, 4176, 4190, 4199 and 4205 described in Table 1 were preparedusing amine salts 4017.01, 4041.01, 4078.01, 4095.01, 4175.01 and4190.01 and corresponding isocyanates or 4-nitrophenyl carbamatefollowing method D of General Schemes for Preparation of TargetCompounds.

Example VI Preparation of Intermediates of Formula 4021.01, 4026.01,4069.01 and 4098.01

R=(L)-Valine, (L)-tert-Leucine, (L)-Cyclhohexylglycine

Isocyanates of type 4021.01, 4026.01, 4069.01 and 4098.01 were preparedaccording the procedure outlined in preparative example I by replacingin step1 the Phenylmagnesium bromide by the known lithio-furan,thiazole, thiophene and oxazole that were reacted with the corresponding(L)-Valine N,O-Dimethylhydroxyl amide or (L)-HomovalineN,O-Dimethylhydroxyl amide or (L)-tert-Leucine N,O-Dimethylhydroxylamide or (L)-Cyclohexylglycine N,O-Dimethylhydroxyl amide.HCV inhibitors 4021, 4024, 4026, 4034, 4069, 4073, 4077, 4098, 4106,4117, 4148, 4158, 4159, 4171, 4174, 4181, 4185, 4189, 4191, 4208 and4209 described in Table 1 were prepared using intermediates of formula4021.01, 4026.01, 4069.01 and 4098.01 according to the generalprocedures described before.

To a −10° C. solution of BocCyclohexylGlycine (10 g, 36 mmol) in DCM(130 mL) was added N,O-Dimethylhydroxylamine hydrochloride (3.7 g, 37.8mmol), NMM (4.2 is mL, 37.8 mmol) and EDCl (7.3 g, 37.8 mmol)portionwise in 15 minutes. The reaction was stirred at this temperaturefor 1 h then HCl (1N, 55 mL) was added. Reaction was extracted with DCM(2 times 50 mL) and combined organic layers was washed with NaHCO3satthen brine. Organic layer was dried over MgSO4, filtered andconcentrated to dryness to provide 4019.02 as a viscous oil (10.8 g).Step2:

To 4019.02 (1.1 g, 3.66 mmol) in Ether (40 mL) was addedCyclopropylmagnesium Bromide (22 mL, 3 equiv, 0.5M in THF) at 0° C. Thereaction was warmed up to RT after 5 min was stirred at RT for when thereaction was quenched by the addition of 1N HCl. Reaction was dilutedwith EtOAc and washed with brine. The organic layer was dried over MgSO4filtered and concentrated to dryness. The residue was purified by HPFCBiotage 25+S, 3% (EtOAc) to 13% EtOAc in Hexane to get 4019.03 (0.676 g,66% yield).Step3:

Isocyanate 4019.01 was prepared following steps 2 and 3 of preparativeexample I._lsocyanates of Formula 4013.01, 4037.01, 4057.01, 4060.01 and4048.01 were prepared as described above by replacing in step2(L)-Cyclohexylglycine N,O-Dimethylhydroxyl amide by (L)-ValineN,O-Dimethylhydroxyl amide or (L)-Homovaline N,O-Dimethylhydroxyl amideor (L)-tert-Leucine N,O-Dimethylhydroxyl amide or (L)-CyclopentylglycineN,O-Dimethylhydroxyl amide or (L)-Cyclobutylglycine N,O-Dimethylhydroxylamide,

HCV inhibitors 4013, 4016, 4018, 4019, 4023, 4032, 4033, 4037, 4039,4040, 4048, 4057, 4060, 4066, 4074, 4084, 4086, 4091, 4092, 4093, 4099,4103, 4105, 4111, 4114, 4123, 4129, 4131, 4132, 4133, 4135, 4138, 4139,4144, 4149, 4150, 4155, 4156, 4161, 4164, 4167, 4169, 4173, 4186, 4187,4192, 4193, 4195, 4197, 4200, 4204, 4206 and 4207 described in Table 1were prepared using intermediates of formula 4019.01, 4013.01, 4037.01,4057.01, 4060.01 and 4048.01 according to the general proceduresdescribed before.

Example VIII Preparation of Intermediates of Formula 4036.01, 4043.01and 4112.01

Isocyanates of Formula 4036.01, 4043.01 and 4112.01 were preparedaccording the procedure outlined in preparative example I withPhenylmagnesium bromide, tert-Butyl lithium and Cyclopropylmagnesiumbromide by replacing in step1 the (L)-Valine N,O-Dimethylhydroxyl amideby the prepared homo-spirocyclohexylglycine N,O-Dimethylhydroxyl amide4036-02 prepared as follow:Step1:

Ester 4036.05 was prepared according T. Suzuki, Chem.Pharm. Bull. 46(7)1116-1124 (1998) from methylenecyclohexane 4036.03 (3.5 g, 36.4 mmol)and chlorosulfonyl isocyanate (1.03 equiv, 37.625 mmol, 3.3 mL) followedby treatment with sulfuric acid. 4.7 g of colorless oil 4036.04 wereobtained.Step2:

To a RT solution of 4036.05 (1 g, 3.71 mmol) in dioxane (10 mL) wasadded (Boc)2O (1.1 equiv, 4 mmol, 0.9 g) then NaHCO3sat followed byK2CO3 to reach Ph=9. After 18 h, reaction was extracted with Et2O.Organic layer was washed with successively with citric acid (10% w/w)and brine. Organic layer was dried over MgSO4, filtered and concentratedunder vacuo. to provide 1 g of 4036.06.Step3:

To a RT solution of 4036.06 (5 g, 18.4 mmol) in Dioxane (30 mL) wasadded 30 mL (1.5 equiv) of 1.0 LiOH. After 5 h, reaction was dilutedwith Et2O and extracted. H2O layer was acidified to Ph=1.5 with 1 N HCland extracted wit EtOAC. Organic layer was washed with brine and driedover MgSO4, filtered and concentrated under vacuo to provide 4.75 g of4036.07.Step4:

To a 0° C. solution of 4036.07 (12.6 mmol, 3.25 g) in DCM 35 mL wasadded HCl. HN(OMe)Me (1.05 equiv, 13.23 mmol, 1.27 g) and NMM (1.05equiv, 13.23 mmol, 1.5 mL). EDCl was added portionwise (1.05 equiv,13.23 mmol, 2.54 g) over 10 min. When reaction completed, HCl 1.5 N wasadded (50 mL) and reaction was extracted with EtOAc, washed with Brine,dried over MgSO4, filtered and concentrated under vacuo to yield: 3.5 gof 4036.02.

HCV inhibitors 4036,4043,4061,4067, 4080,4112 and 4115 described inTable 1 were prepared using intermediates of formula 4036.01, 4043.01and 4112.01 according to the general procedures described before.

Example IX Preparation of compound of Formula 4025

To amide 4019.02 (0.8 g, 2.66 mmol) in ether (50 mL) was addedisopropenylmagnesium Bromide (Aldrich Chemical Co., Milwaukee, Wis., USA19 mL, 9.5 mmol, 3.6 equiv) at 0° C. The reaction was warmed up to RTafter 5 min and stirred at RT for 3 hrs then quenched by the addition of1N HCl. reaction was diluted with EtOAc and washed with brine. Theorganic layer was dried over MgSO4 filtered and concentrated down. Theresidue was purified it by HPFC with 10% EtOAc in hexane to get 0.304 gof product 4025.01 (Yield=40.6%).Trimethylsulfoxonium iodide (237 mg, 1.08 mmol) was added in one portionto a suspension of NaH i(43 mg, 1.08 mmol, 60% in oil) in DMF at RT andstirred for 30 min under N2. The reaction mixture was cooled to −30° C.A solution of ketone 4025.01 (304 mg, 1.08 mmol) in 1 mL DMF was addeddropwise to the mixture and stirred at −30° C.˜0° C. for 2 hrs then 3 mLof H2O was added dropwise at −20° C. to the reaction mixture. Reactionwas diluted with EtOAc. and organic layer was washed with aq. NH4Cl, H2Oand brine. Organic layer was dried over MgSO4, filtered and concentrateddown. The residue was purified it by HPFC with 0˜1% EtOAC in CH2Cl2 togive 176 mg of ketone 4025 (Yield=54%). Optical Rotation: [alpha]=+87.12(c=7.5 mg/2 mL, 20° C., CHCl3).Isocyanate 4025.03 was prepared according the procedure described instep3 of Preparative Example VII (scheme VII).HCV inhibitors 4025, 4053 and 4127 described in Table 1 were preparedusing intermediate of formula 4025.03 according to the generalprocedures described before.

Example X Preparation of Compound of Formula 4179

HCV inhibitors 4179 described in Table 1 was prepared according theScheme X above using intermediate of formula 4179.01 prepared accordingthe procedure describe below.Step1:

To a mixture of (S)-hydroxyisovaleric acid (4.4 g, 37 mmol),dimethylamine hydrochloride (3.0 g, 37 mmol), and1-hydroxy-1H-benzotriazole (5 g, 37 mmol) in THF (20 mL) was addeddiisopropylethylamine (6.4 mL, 37 mmol) dropwise at −20 C thendicyclohexylcarbodiimide (8 g, 39 mmol) was added at once, and themixture was stirred at RT overnight. After 18 hours, the formedprecipitate was filtered off and washed with EtOAc. the combinedfiltrates were concentrated in vacuo and residue was purified by biotage75+S column (35% EtOAc/Hex). to yield 5.3 g of amide 4179.03.Step2:

To 4179.03 (1.5 g, 10 mmol) in dry THF (30 mL) was added phenylmagnesiumbromide (10 mL, 3.0M in Ether) at 0 C. The reaction was warmed up to RTgradually. and stirred at RT overnight then was quenched by the additionof 1 N HCl, diluted with EtOAc and washed with brine. The organic layerwas dried over MgSO4. purified by HPFC biotage 25+M with 15-25% EtOAc inHex. to yield 1.6 g of 4179.04.Step3:

To chloroformate 4179.05 in CH2Cl2 at 0C was added dropwise a solutionof 4179.04 (0.8 g, 4.5 mmol) and pyridine (0.5 mL). The reaction waswarmed up to 40 C with hot water and stirred for 1.5 hr then dilutedwith EtOAc, washed with sat. NaHCO3, CuSO4, and brine. dried over MgSO4,filtered, concentrated and purified by column biotage 25+S (40-60%EtOAc/Hex.).to yield 580 mg of 4179.01.

All other HCV inhibitors reported in Table 1 can be prepared accordingprocedures described above in examples I to VIII. TABLE 1 KETONES CmpdKi* # Table 1: Ketones MW Range 4010

610 A 4011

624 A 4012

640 A 4013

588 A 4016

574 A 4017

625 A 4018

615 A 4019

628 A 4020

626 A 4021

617 A 4022

611 A 4023

614 A 4024

658 A 4025

628 A 4026

616 A 4027

624 A 4028

636 A 4029

653 A 4030

631 A 4031

651 A 4032

652 A 4033

656 A 4034

695 A 4035

650 A 4036

650 A 4037

588 A 4038

626 A 4039

642 A 4040

640 A 4041

689 A 4042

688 A 4043

630 A 4044

624 A 4045

640 A 4046

622 A 4047

616 A 4048

586 A 4051

664 A 4052

624 A 4053

692 A 4054

576 A 4055

636 A 4056

590 A 4057

588 A 4058

588 A 4059

599 A 4060

600 A 4061

644 A 4062

648 A 4063

616 A 4064

628 A 4065

651 A 4066

654 A 4067

668 A 4068

638 A 4069

600 A 4070

548 A 4071

656 A 4072

641 A 4073

657 A 4074

588 A 4075

644 A 4076

638 A 4077

631 A 4078

611 A 4079

638 A 4080

658 A 4081

588 A 4082

624 A 4083

668 A 4084

634 A 4085

630 A 4086

682 A 4087

631 A 4088

668 A 4089

588 A 4090

693 A 4091

602 A 4092

674 A 4093

656 A 4094

640 A 4095

611 A 4096

625 A 4097

652 A 4098

601 A 4099

670 A 4100

690 A 4101

639 A 4102

638 A 4103

602 A 4104

716 A 4105

643 A 4106

644 A 4108

590 A 4109

652 A 4110

650 A 4111

654 A 4112

614 A 4113

625 A 4114

588 A 4115

670 A 4117

645 A 4118

604 A 4119

598 A 4120

646 A 4121

716 A 4122

681 A 4123

662 A 4124

616 A 4125

644 A 4126

664 A 4127

642 A 4128

688 A 4129

696 A 4130

678 A 4131

616 A 4132

702 A 4133

658 A 4134

669 A 4135

614 A 4136

653 A 4137

618 A 4138

616 A 4139

656 A 4140

721 A 4141

652 A 4143

604 A 4144

722 A 4145

659 A 4146

616 A 4148

631 A 4149

616 A 4150

630 A 4151

668 A 4152

624 A 4153

650 A 4154

624 A 4155

684 A 4156

588 A 4157

667 A 4158

685 A 4159

644 A 4160

702 A 4161

644 A 4162

632 A 4163

637 A 4164

660 A 4165

662 A 4166

546 A 4167

602 A 4168

639 A 4169

682 A 4170

639 A 4171

699 A 4172

625 A 4173

628 B 4174

673 B 4175

653 B 4176

646 B 4177

706 B 4178

650 B 4179

611 B 4180

618 B 4181

631 B 4182

622 B 4183

636 B 4184

610 B 4185

687 B 4186

604 B 4187

576 B 4188

578 B 4189

642 B 4190

637 B 4191

659 B 4192

590 B 4193

632 B 4194

622 B 4195

642 B 4196

604 B 4197

658 B 4198

646 B 4199

657 B 4200

698 B 4201

662 B 4203

660 C 4204

620 C 4205

665 C 4206

724 C 4207

684 C 4208

701 C 4209

647 C

PREPARATION OF SPECIFIC EXAMPLES FROM TABLE 2 Example XI Preparation ofCompound of Formula 4289 and 4294

Step1:To a RT solution of Ketone 4010.01 prepared in step 1 of preparativeexample III (2 mmol, 554 mg) in Pyridine (10 mL) was addedO-methylhydroxylamine hydrochloride (2 equiv, 4 mmol, 334 mg). Theresulting mixture was heated to 50° C. for 18 hr. After 18 h, TLC showedno starting material and a slightly less polar product and the reactionwas concentrated under vacuo to remove pyridine. The resulting whiteslurry was dissolved in DCM and washed with HCl 1.0 N (10 mL). DCM layerwas then washed with aqueous CuSO4sat and brine. Organic layer was driedover MgSO4, filtered and concentrated under vacuo. The residue waspurified by HPFC Biotage 25+M. HPFC, 3% (EtOAc) to 12% (EtOAc) inHexane, Purification provided 2 isomers 4289.01 and 4294.01 in a 80/20E/Z ratio.Step2To 4294.01(60 mg) in CH2Cl2 (3 mL) under N2 was added TFA (1 mL) at RT.The reaction was stirred at RT for 20 min and was concentrated todryness and placed under high vacuum overnight. 40 mg of product 4294.02was obtained.Identical procedure was applied to the other isomer 4289.01 to produceamine salt 4289.02.Step3:HCV inhibitors 4294 and 4289 in table 2 were prepared using amine salts4294.02 and 4289.02 and corresponding isocyanates or 4-nitrophenylcarbamate following method D of General Schemes for Preparation ofTarget Compounds.

Example XII Preparation of Compound of Formula 4291.02, 4297.02 and4290.02

Amines salts of Formula 4291.02, 4297.02 and 4290.02 were preparedaccording step 1 and 2 of preparative example XI by replacingO-methylhydroxylamine hydrochloride by methylhydroxylamine hydrochlorideand ketone 4010.01 by the corresponding (L) Cyclohexylglycine ketone4019.03 of preparative example VII and the corresponding (L) Valineketone.

HCV inhibitors 4290, 4291, 4292, 4293, 4295, 4297 and 4298 in table 2were prepared using amine salts 4291.02, 4297.02 and 4290.02 and thecorresponding isocyanates or 4-nitrophenyl carbamate following method Dof General Schemes for Preparation of Target Compounds: TABLE 2 OximesCmpd Ki* # MW Range 4289

639 A 4290

629 A 4291

589 B 4292

629 B 4293

603 B 4294

639 B 4295

603 B 4296

667 B 4297

643 B 4298

643 B

PREPARATION OF SPECIFIC EXAMPLES FROM TABLE 3 Example XIII Preparationof Compound of Formula 4488

Step 1:

To a RT solution of Boc-1-amino-cyclohexanecarboxylic acid 4488.01 (3 g,13.38 mmol) in CH₂Cl₂ (30 mL) was added Benzyl alcohol (3 equiv, 4 mL),DMAP (1.01 equiv, 1.65 g) and DCC (1.0 M solution in DCM, 1.01 equiv,13.5 mL). The reaction was stirred at RT for 48 h. The insolublematerial was removed by filtration and crude was concentrated todryness. The residue was purified by flash chromatography (5% to 10%EtOAc in Hexanes, Biotage 40M). Purification furnished 4488.02 (3.64 g).(M+H)=334.Step2:

To a RT solution of 4488.02 (3.6 g, 10.8 mmol) was added 100 mL of a 4.0N HCl solution in Dioxane. Reaction was stirred at RT for 1 h then 18 hto observe completion. After 18 h, reaction was diluted with Heptanesand Et2O and the precipitate was filtered off and rinsed with Et2O anddried under a N2 flow. Reaction yielded 2.6 g of 4488.03 as a whitepowder.Step3:

To a 0° C. solution of 4488.03 (2.5 mmol, 666 mg) in CH2Cl2 (25 ml) andNaHCO3sat (20 mL) was added Phosgene (2 equiv, 20% in PhMe, 2.5 mL). Thereaction was warmed-up to RT and stirred for 2 hours. The organic phasewas separated and was then dried over anhydrous MgSO4 and concentratedto half volume under vacuum with cooling bath. The solution was thendiluted to 25 mL and used as a 0.1 M solution of 4488.04.Step4:

To a 0° C. solution of amine 4488.05 prepared following general method C(60 mg, 0.135 mmol) in CH2Cl2 (5 ml) was added DIPEA (8 equiv., 1.08mmol, 0.2 mL) and isocyanate 4488.04 (3 equiv., 0.406 mmol, 4 mL). Thereaction was warmed-up to RT and stirred for 2 hours. Reaction wasdiluted with EtOAc and washed successively with citric acid (10% w/w)and brine. Organic layer was dried over MgSO4, filtered and concentratedunder vacuo. The residue was purified by preparative plate using 40%Acetone in Hexane as eluant. Purification furnished 32 mg of product HCVinhibitor 4488. (M+H)=667.

Example XIV Preparation of Compound of Formula 4303

All tert-Butyl esters included in Table 3 were prepared according thefollowing procedure. Commercially available amino tert-Butyl esterhydrochloride like (but mot limited to) (L)-cyclohexylglycine,(L)-Valine, (L)-tert-Leucine tert-Butyl ester hydrochloride were reactedwith phosgene as outlined in step 3 of preparative example XIII toproduce the corresponding isocyanate (4303.01 was prepared fromcommercially available (L)-Valine tert-Butyl ester hydrochloride).Isocyanates were reacted with various amines like 4303.01 preparedfollowing general method C to produce HCV inhibitors like 4303 listed inTable 3.

All other HCV inhibitors listed in Table 3 were prepared accordingprocedure described in Preparative Example XIII by replacing in step 1benzyl alcohol with other commercially available alcohols (primary,secondary and tertiary) and Boc-1-amino-cyclohexanecarboxylic acid4488.01 with other commercially amino acid like (but mot limited to)(L)-cyclohexylglycine, (L)-Valine or (L)-tert-Leucine. TABLE 3 EstersCmpd Ki* # MW Range 4300

684 A 4301

644 A 4302

646 A 4303

606 A 4304

670 A 4305

644 A 4306

618 A 4307

606 A 4308

618 A 4309

634 A 4310

672 A 4311

658 A 4312

660 A 4313

660 A 4314

666 A 4315

654 A 4316

632 A 4317

646 A 4318

680 A 4319

630 A 4320

658 A 4321

638 A 4322

644 A 4323

616 A 4324

675 A 4325

646 A 4326

658 A 4327

592 A 4328

652 A 4329

604 A 4330

660 A 4331

660 A 4332

618 A 4333

630 A 4334

668 A 4335

661 A 4336

620 A 4337

640 A 4338

668 A 4339

646 A 4340

618 A 4341

692 A 4342

632 A 4343

604 A 4344

660 A 4345

721 A 4346

602 A 4347

670 A 4348

684 A 4349

670 A 4350

666 A 4351

672 A 4352

680 A 4353

720 A 4354

707 A 4355

694 A 4356

680 A 4357

687 A 4358

604 A 4359

632 A 4360

632 A 4361

642 A 4362

723 A 4363

706 A 4364

680 A 4365

687 A 4366

590 A 4367

588 A 4368

634 A 4369

668 A 4370

674 A 4371

658 A 4372

632 A 4373

648 A 4374

694 A 4375

661 A 4376

660 A 4377

592 A 4378

720 A 4379

658 A 4380

632 A 4381

686 A 4382

684 A 4383

648 A 4384

632 A 4385

682 A 4386

668 A 4387

618 A 4388

620 A 4389

634 A 4390

709 A 4391

735 A 4392

640 A 4393

721 A 4394

701 A 4395

668 A 4396

592 A 4397

658 A 4398

608 A 4399

708 A 4400

680 A 4401

706 A 4402

674 A 4403

672 A 4404

662 A 4405

656 A 4406

686 A 4407

660 A 4408

634 A 4409

632 A 4410

590 A 4411

654 A 4412

606 A 4413

658 A 4414

620 A 4415

662 A 4416

648 A 4417

694 A 4418

666 A 4419

660 A 4420

680 A 4421

658 A 4422

646 A 4423

618 A 4424

618 A 4425

682 A 4426

672 A 4427

712 A 4428

646 A 4429

647 A 4430

656 A 4431

702 A 4432

736 A 4433

656 A 4434

676 A 4435

704 A 4436

709 A 4437

633 A 4438

648 A 4439

682 A 4440

686 A 4441

632 A 4442

646 A 4443

698 A 4444

648 A 4445

672 A 4446

700 A 4447

630 A 4448

656 A 4449

721 A 4450

674 A 4451

680 A 4452

696 A 4453

680 A 4454

668 A 4455

708 A 4456

688 A 4457

674 A 4458

688 A 4459

646 A 4460

686 A 4461

700 A 4462

686 A 4463

618 A 4464

654 A 4465

684 A 4466

632 A 4467

646 A 4468

646 A 4469

616 A 4470

678 A 4471

654 A 4472

690 A 4473

730 A 4474

618 A 4475

660 A 4476

670 A 4477

678 A 4478

660 A 4479

688 A 4480

708 A 4481

644 A 4482

710 A 4483

662 A 4484

768 A 4485

676 A 4486

732 A 4487

734 A 4488

666 A 4489

634 A 4490

680 A 4491

668 A 4492

702 A 4493

726 A 4494

698 A 4495

690 A 4496

688 A 4497

652 A 4498

748 A 4499

654 A 4500

654 A 4501

616 A 4502

692 A 4503

682 A 4504

746 A 4505

658 A 4506

632 A 4507

670 A 4508

646 A 4509

672 A 4510

684 A 4511

704 A 4512

702 A 4513

630 A 4514

694 A 4515

769 A 4516

626 A 4517

631 A 4518

695 A 4519

694 A 4520

684 A 4522

666 A 4523

766 A 4524

660 A 4525

646 A 4526

686 A 4527

721 A 4528

656 A 4529

707 A 4530

735 A 4531

646 A 4532

646 A 4533

618 A 4534

626 A 4535

708 A 4536

680 A 4537

701 A 4538

721 A 4539

692 B 4540

680 B 4541

692 B 4542

654 B 4543

614 B 4544

680 B 4545

640 B 4546

708 B 4547

706 B 4548

780 B 4549

794 B 4550

722 B 4551

646 B 4552

734 B 4553

668 B 4554

700 B 4555

654 B 4556

706 B 4557

734 B 4558

688 B 4559

634 B 4560

660 B 4561

675 B 4562

668 B 4563

683 B 4564

654 B 4565

605 B 4566

614 B 4567

690 B 4568

680 B 4569

701 B 4570

684 B 4571

635 B 4572

628 B 4573

682 B 4574

724 B 4575

710 B 4576

682 B 4577

690 B 4578

646 B 4579

710 B 4580

660 B 4581

657 B 4582

702 B 4583

682 B 4584

682 B 4585

714 B 4586

722 B 4587

634 B 4588

640 B 4589

680 B 4590

718 B 4591

726 B 4592

654 B 4593

694 B 4594

617 B 4595

790 B 4596

766 B 4597

710 B 4598

688 B 4599

652 B 4600

660 B 4601

668 B 4602

624 B 4603

640 B 4604

674 B 4605

707 B 4606

659 B 4607

674 B 4608

710 B 4609

660 B 4610

697 B 4611

694 B 4612

702 B 4613

674 B 4614

708 B 4615

692 B 4616

674 B 4617

634 B 4618

660 B 4619

662 B 4620

670 B 4621

704 B 4622

668 B 4623

682 B 4624

631 B 4625

680 B 4626

668 B 4627

680 B 4628

722 B 4629

658 B 4630

709 C 4631

718 C 4632

666 C 4633

654 C 4634

654 C 4635

710 C 4636

724 C 4637

690 C 4638

660 C 4639

648 C 4640

707 C 4641

666 C 4642

668 C 4643

722 C 4644

591 C 4645

730 C 4646

648 C 4647

660 C 4648

646 C 4649

672 C 4650

648 C 4651

756 C 4652

800 C 4653

576 C 4654

714 C 4655

682 C 4657

680 C 4658

668 C 4659

824 C 4660

648 C 4661

742 C 4662

662 C 4663

694 C 4665

782 C 4666

626 C

PREPARATION OF SPECIFIC EXAMPLES FROM TABLE 4 Example XV Preparation ofCompound of Formula 4700

To a solution of ester 4488 of table 3 (28 mg, 0.042 mmol) in ethanol (5ml) was added 10% Pd/C catalyst (20% w/w, 6 mg). The resultingsuspension was hydrogenated until thin layer chromatography indicatedcomplete consumption of the starting material (˜3 hrs). The catalyst wasremoved by filtration through a pad of celite and washed with EtOAc. Thecombined filtrate and washings were evaporated under vacuum to drynessto provide the desired product 4700 (25 mg). (M+H)=576.

Example XVI Preparation of Compound of Formula 4703

To ester 4309 of table 3 (70 mg) was 5 mL of HCOOH (98%). The reactionwas stirred at RT until thin layer chromatography indicated completeconsumption of the starting material (˜2 hrs). The volatiles wereevaporated under vacuum to dryness to provide the desired product 4703(62 mg). (M+H)=578.

All other HCV inhibitors of Table 4 were prepared according proceduredescribed in preparative examples XV and XVI above. TABLE 4 Cmpd Ki* #Carboxylic Acids MW Range 4700

576 A 4701

632 A 4702

619 A 4703

577 A 4704

624 A 4705

679 A 4706

638 A 4707

602 A 4708

564 A 4709

636 A 4710

590 A 4711

590 A 4712

588 A 4713

562 A 4714

606 A 4715

668 A 4716

578 A 4717

598 A 4718

564 A 4719

578 A 4720

654 A 4721

558 A 4722

668 A 4723

578 B 4724

534 B 4725

536 B 4726

572 B 4727

564 B 4728

604 B 4729

564 B 4730

548 C

PREPARATION OF SPECIFIC EXAMPLES FROM TABLE 5 Example XVII Preparationof Compound of Formula 4888

To a RT solution of 4700 (Table 4) of preparative example XV (0.02 g,0.035 mmol) in CH2Cl2 (2 mL) was added Benzylamine. HCl (1.2 equiv,0.042 mmol, 6 mg), HATU (1.2 equiv, 0.042 mmol, 16 mg) then DIPEA (5equiv, 0.175 mmol, 0.031 mL). The reaction was stirred RT for 2 hoursthen was diluted with EtOAc and washed successively with citric acid(10% w/w), NaHCO3 and brine. Organic layer was dried over MgSO4,filtered and concentrated under vacuo. The residue was purified bypreparative plate using 40% Acetone in Hexane as eluant. 4 mg of desiredproduct 4888 were obtained. (M+H)=665.

HCV inhibitors 4801 to 4917 of Table 5 have been prepared using theprocedure described in example XVII.

Example XVIII Preparation of Compound of Formula 4800

Part I: Preparation of Intermediate of Formula 4800.05

To a −20° C. solution of Boc-L-Valine 4800.01 (1.1 g, 5 mmol) in DCM (20mL) was added HATU (1.2 equiv, 6 mmol, 2.3 g), DIPEA (5 equiv, 25 mmol,4.4 mL) then Benzene sulfonamide (1.1 equiv, 5.5 mmol, 0.86 g). Reactionwas stirred at this temp for 48 h. The reaction was diluted with EtOAcand washed successively with citric acid (10% w/w), NaHCO3 and brine.Organic layer was dried over MgSO4, filtered and concentrated undervacuo. Recrystallization occurred with a mixture on DCM and MeOH. 600 mgof white crystals (4800.02) were obtained with 1.5 g of oily residue.The 600 mg were used in the next step.

4.0 N HCl Dioxane (25 mL) was added to 4800.02 (600 mg). Reaction wasstirred at RT until no starting material was detected by TLC (2 h).Then, Et2O was added and the resulting white powder was filtered off anddried under a N2 flow to yield=0.46 g (1.57 mmol) of 4800.03.

To a 0° C. solution of isocyanate 4800.04 (prepared as described in step3 of preparative example XIII by replacingBoc-1-amino-cyclohexanecarboxylic acid 4488.01 of step 1 byBoc-L-Tert-Leucine, 0.7 mmol, 3.5 mL) in CH2Cl2 (2 ml) was added 4800.03(180 mg, 0.61 mmol) then DIPEA (1.1 equiv., 0.7 mmol, 0.122 mL). Thereaction was warmed-up to RT and stirred over the week-end. After 48 h,reaction was concentrated to dryness and the oily residue was purifiedby HPFC Biotage 25+S, 50% to 100% EtOAc in Hexane. Purification provided110 mg of 4800.05.

To a solution of 4800.05 (0.11 g, 0.219 mmol) in EtOAc (5 ml) was added10% Pd/C catalyst (15% w/w, 16 mg). The resulting suspension washydrogenated until thin layer chromatography indicated completeconsumption of the starting material (˜3 hrs). The catalyst was removedby filtration through a pad of celite and washed with EtOAc. Thecombined filtrate and washings were evaporated under vacuum to drynessto provide the desired product 4800.06 (85 mg).Part II: Preparation of Intermediate of Formula 4800.08

To a −20° C. solution of acid 4800.07 (prepared following the method ofR. Zhang and J. S. Madalengoitia (J. Org. Chem. 1999, 64, 330), 5.1 g,20 mmol) in DCM (200 mL) was added HATU (1.05 equiv, 21 mmol, 8 g),amine salt 12.03 (prepared as described in Preparation of intermediates,preparation of P1-P′ moieties, 1.0 equiv, 20 mmol, 3.893 g). After 10min at −20° C., DIPEA (5 equiv, 100 mmol, 17.4 mL) was added, andreaction was stirred at this temp for 16 hrs then the reaction wasdiluted with EtOAc and washed successively with NaHCO3, citric acid (10%w/w) and brine. Organic layer was dried over MgSO4, filtered andconcentrated under vacuo. Purification Biotage 75+M (3.5 l of 1/1Hex/EtOAC) then 100% EtOAc. provided 12 g of a light brown oil that wasused directly in the following step. To a RT solution of this crude oil(12 g) was added 100 mL of a 4.0 N HCl solution in Dioxane. Reaction wasstirred at RT for 1 h to observe completion then diluted with Heptanesand concentrated to dryness under vacuo to furnish 10.4 g of dark brownoil 4800.08 that was used directly for the preparation of compound offormula 4800.09.Part III: Preparation of Compound of Formula 4800:

To a −20° C. solution of 4800.06 (85 mg, 0.2 mmol) in DCM (50 mL) wasadded HATU (1.2 equiv, 0.24 mmol, 92 mg), crude amine salt 4800.08 (1.2equiv, 0.24 mmol, 80 mg). After 10 min at −20° C., DIPEA (5 equiv, 1mmol, 0.22 mL) was added. Reaction was stirred at this temperature for18 h then reaction was diluted with EtOAc and washed successively withcitric acid (10% w/w) and brine. Organic layer was dried over MgSO4,filtered and concentrated under vacuo. 250 mg of crude 4800.09 wereobtained. (M+H)=691.

To a 0° C. solution of crude 4800.09 (0.25 g, 0.2 mmol) in DMSO/PhMe (12mL) was added EDCl (10 equiv, 1 mmol, 400 mg) and Dichloroacetic acid (5equiv, 1 mmol, 0.08 mL). The reaction was warmed-up to RT gradually andstirred at this temperature. After 4 h, reaction was diluted with waterand the 2 phases were separated. Organic layer was washed with sat.Na2S2O3 (2 TIMES), NaHCO3 and brine. Organic layer was dried over MgSO4,filtered and concentrated under vacuo. The residue was purified by HPFCBiotage 12 S, 2% to 6% MeOH in DCM. Purification furnished 35 mg ofcompound of formula 4800. TABLE 5 Cmpd Ki* # Amides MW Range 4800

689 A 4801

693 A 4802

694 A 4803

605 A 4804

619 A 4805

667 A 4806

605 A 4807

631 A 4808

645 A 4809

679 A 4810

591 A 4811

631 A 4812

617 A 4813

679 A 4814

695 A 4815

696 A 4816

712 A 4817

591 A 4818

633 A 4819

631 A 4820

681 A 4821

681 A 4822

712 A 4823

605 A 4824

577 A 4825

563 A 4826

631 A 4827

633 A 4828

577 A 4829

631 A 4830

645 A 4831

617 A 4832

674 A 4833

781 A 4834

706 A 4835

619 A 4836

631 A 4837

619 A 4838

659 A 4839

617 A 4840

617 A 4842

633 A 4843

728 A 4844

665 A 4845

632 A 4846

617 A 4847

603 A 4848

617 A 4849

619 A 4850

633 A 4851

617 A 4852

633 A 4853

603 A 4854

631 A 4855

765 A 4856

619 A 4857

591 A 4858

605 A 4859

617 A 4860

665 A 4861

603 A 4862

734 A 4863

653 A 4864

647 A 4865

671 A 4866

699 A 4867

659 A 4868

687 A 4869

603 A 4871

738 A 4872

591 A 4873

647 A 4874

671 A 4875

645 A 4876

619 A 4877

695 A 4878

687 A 4879

673 A 4880

659 A 4881

647 A 4882

667 A 4883

695 A 4884

661 A 4885

646 A 4886

679 A 4887

733 A 4888

665 A 4889

699 A 4890

659 A 4891

655 A 4892

677 A 4893

750 A 4894

655 A 4895

615 A 4896

631 A 4897

629 A 4898

659 A 4899

645 A 4900

731 A 4901

685 A 4902

645 A 4903

613 A 4904

754 B 4905

661 B 4906

535 B 4907

705 B 4908

679 B 4909

721 B 4910

715 B 4911

645 B 4912

679 B 4913

563 B 4914

693 C 4915

734 C 4916

603 C 4917

719 C

Example XIX Preparation of General Intermediates of Tables 6.1, 6.2 and6.3

Part I: Preparation of Intermediate of Table 6.1

(Heterocyclyl)Methyl Chlorides

5-(Dimethylaminomethyl)furfuryl chloride was prepared from commerciallyavailable 5-(dimethylaminomethyl)furfuryl alcohol (Aldrich Chemical Co.,Milwaukee, Wis., USA) as reported (II Farmaco, Ed. Sci., 1982, 37, 398).

2-, 3-, And 4-picolyl chlorides were prepared from the commerciallyavailable hydrochloride salts (Aldrich Chemical Co., Milwaukee, Wis.,USA) by partitioning them with cold 2.5 N NaOH and ether, drying theether extract with MgSO₄, and concentrating the solution in a 15° C.water bath, all immediately before use.

2-Chloromethylfuran was prepared from SOCl₂ in Et₂O as reported (JACS,(1928), 50, 1955). 3-chloromethylfuran was prepared similarly, except asolution of alcohol and pyridine was added to a solution of SOCl₂ toprevent excessive formation of sulfonate diester. In both casesdistillation was necessary to effect rearrangement of the initialchlorosulfonate isolate. Both distilled halides were immediately storedin ether (˜1 M) with a little solid K₂CO₃ at −20° C. These solutionswere stable for at least 24 hours.

2- And 3-chloromethythiophene were prepared using the same procedures asfor 2- and 3-chloromethylfuran, except distillation was not necessary,since the chlorosulfonates transformed spontaneously under the reactionconditions. The dried extract solutions were rapidly suction-filteredthrough silica gel pads to effect sufficient purification. The filtrateswere stored cold, and concentrated carefully immediately before use.

Methyl [2-(4-Pyridylmethyl)Cyclohexane]Carboxylate

A solution of 20 mL of 2 M LDA/THF-heptane (Acros Chemical Co.) in 50 mLof THF was cooled to −70° C., and 6 g of methyl cyclohexanecarboxylate17018 was added drop wise at <−60° C. After an additional 0.5 hrstirring at −70° C., 5.1 g of 4-picolyl chloride in 40 mL ether wasadded drop wise at <−60° C. The temperature was then allowed to riseslowly to room temperature over 2 hr, and stirred an additional 2 hr.The reaction was quenched in a cold mixture of 200 mL 20% aqueous KH₂PO4and 5 mL 12 N HCl, the mixture was extracted with EtOAc, the extract waswashed with brine, and then dried with MgSO₄. The mixture was filtered,the filtrate was evaporated, the residue was evaporated twice fromxylene, and the final residue was chromatographed on silica gel (1:4Et₂O—CH₂Cl₂) to obtain 3.0 g of an amber oil 17020 (30%): H¹-NMR (CDCl₃)δ 8.46 (d, 2H, Δv=6.0), 6.98 (d, 2H, Δv=6.0), 3.62 (s, 3H), 2.79 (s,2H), 2.05 (m, 2H), 1.7-1.2 (mm, 8H).

Methyl [2-(Heteroarylmethyl)Cyclohexane]Carboxylates

The procedure of the preceding example was applied to the aryl methylchlorides to afford the corresponding substitutedcyclohexanecarboxylates as summarized in the following Table 6.1. TABLE6.1 Product H¹-NMR Starting Chromatography (CDCL₃) δ (Δv in halidesystem Yield Product Hz)

17021 1:3 Et₂O—CH₂Cl₂to 1:1 acetone- CH₂Cl₂ 31

17028 8.45(d of d, 1H, Δv₁=4.8, Δv_(□)=1.8), 7.35(d of t, 1H, Δv₁=7.8,Δv₂=1.8), 7.18(d of d, 1H, Δv₁=7.8, Δv₂=4.8), 3.62(s, 3H), 2.79 (s, 2H),2.1(m, 2H), 1.7-1.2(mm, 8H)

17022 1:3 Et₂O—CH₂Cl₂to 1:1 acetone- CH₂Cl₂ 58

17029 8.50(br d, 1H, Δv=4.5, 7.55(t+, 1H, Δv₁=7.6, Δv₂=1.8), 7.10(d ofd+, Δv₁=7.6, Δv₂=4.5, Δv₃=nd), 7.01(d, Δv=7.6), 3.64(s, 3H), 2.98 (s,2H), 2.1(m, 2H), 1.7-1.2(mm, 8H)

17023 Rapid silica pad filtration in 1:1 hexane-toluene 52

17030 7.28(br d, 1H, Δv=1.8, 6.26(d of d, 1H, Δv₁=3.0, Δv₂=1.8), 5.97(d,1H, Δv=3.0), 3.66 (s, 3H), 2.83(s, 2H), 2.05(m, 2H), 1.7-1.2(mm, 8H)

17024 Short column, EtOAc to acetone None: extracted at pH 5.0 aftersaturating aqueous with NaCl 30

17031 6.05(d, 1H, Δv=3.0), 5.89(d, 1H), 3.66(s, 3H), 3.40(s, 2H), 2.81(s, 2H), 2.23(s, 6H), 2.05(m, 2H), 1.7-1.2(mm, 8H)

17025 Rapid silica pad filtration in 1:1 hexane-toluene 81

17032 7.34(m, 1H), 7.18 (br s, 1H), 6.17(br s, 1H), 3.65(s 3H), 2.62(s,2H), 2.1 (m, 2H), 1.7-1.2 (mm, 8H)

17026 4:96 Et₂O-hexane 75

17033 7.11(d+, 1H, Δv=5.1), 6.91(d of d, 1H, Δ₁v=5.1, Δv₂=3.6), 6.72(dof d, 1H, Δ₁v=3.6, Δv₂=0.9), 3.67(s 3H), 3.04(s, 2H), 2.1(m, 2H),1.7-1.2 (mm, 8H)

17027 3:97 Et₂O-hexane 53

17034 7.20(d of d, 1H, Δv₁=5.0, Δv₂=3.0), 6.89(br s, 1H), 6.80(d of d,1H, Δv₁=5.0, Δv₂=1.5), 3.63(s 3H), 2.83 (s, 2H), 2.1(m, 2H), 1.7-1.2(mm,8H)Part II: Preparation of Intermediates of Table 6.2:

Preparative Example 17035 Preparation of Intermediate of Formula 17035[2-(4-Pyridylmethyl)Cyclohexane]Carboxylic Acid

A solution of 3.4 g ester 17020 of the previous example in 20 mL ofdioxane was treated with 30 mL of 1 N aqueous LiOH, and the mixture wasstirred at 100° C. for 6 hr. The mixture was quenched in ice-water,extracted with ether, and the cold aqueous was slowly acidified to pH 4with 3 N HCl. The precipitate was filtered, washed with water, and driedto leave 2.8 g (58%) product acid 17035: H¹-NMR (DMSO-d₆) δ 8.42 (d,2H), 7.08 (d, 2H), 2.73 (s, 2H), 1.9-1.1 (mm, 10H). A portion wascrystallized from EtOH: mp: 240-242° C.; elemental analysis confirmed:CHN. Same procedure was applied for the preparation of intermediates17036 and 17037 of table 6.2.

[1-(Heteroarylmethyl)Cyclohexane]Carboxylic Acids

The procedure of the preceding example was applied to the esters (17038,17039, 17040, 17041, 17042) from Table 6.2 except that the acidifiedaqueous extract (pH 3.5-4.0) was extracted with EtOAc, after saturatingwith NaCl in the case of the two pyridyl products 17036 and 17037. Theextract was evaporated to leave the product acids. Portions werecrystallized for analysis as summarized in the following Table 6.2.TABLE 6.2 Product H¹-NMR crystal- Starting Yield (CDCL₃) lization mpester Product % δ ((ppm); Δv in Hz solvent (° C.) Elemanal 17028

17036 31 8.42(br s, 2H), 7.57(d+, 1H, Δv₁=7.5, Δv₂=1.8), 7.27(d of d,1H, Δv₁=7.5, Δv₂=2.7), 2.83(s, 2H), 2.1(m, 2H), 1.7-1.2 (mm, 8H)CH₃CCl₃- cyclohexane 155-7 CHN 17029

17037 58 8.62(d, 1H, Δv=5.1), 7.70(t+, 1H, Δv₁=7.5, Δv₂=1.8), 7.22(m,2H), 3.10(s, 2H), 2.1(m, 2H), 1.6-1.3(mm, 8H) EtOH- (i-Pr)₂O 137-8 CHN17030

17038 52 7.29(br s, 1H), 6.27(d of d, 1H, Δv₁=3.0, Δv₂=1.8), 6.05(d, 1H,Δv=3.0), 2.90(s, 2H), 2.0(m, 2H), 1.7-1.2 (mm,8H) na oil CH 17031

17039 30 6.47(d, 1H, Δv=3.0), 6.08(d, 1H, Δv=3.0), 4.14(s, 2H), 2.84(s,2H), 2.77(S, 6H), 2.1 (m, 2H), 1.7-1.1(mm, 8H) CH₃CCl₃- cyclohexane133-5 na 17032

17040 81 7.34(br s, 1H), 7.22(br s, 1H), 6.22(br s, 1H), 2.67(s, 2H),2.0(m, 2H), 1.7-1.2(mm, 8H) na oil CH 17033

17041 75 7.14(d of d, 1H, Δv₁=5.2, Δv₂=1.0), 6.93(d of d, 1H, Δv₁=5.2,Δv₂=3.6), 6.80(d+, 1H, Δv₁=3.6, Δv₂=nod²), 3.08³(2H), 2.1(m, 2H),1.7-1.2 (mm, 8H) cyclohexane- hexane/ −10° C. 64-7¹ CH 17034

17042 53 7.22(d of d, 1H, Δv₁=5.0, Δv₂=2.5), 6.96(d+, 1H, Δv₁=2.5,Δv₂=nod), 6.89 (d of d, 1H, Δv₁=5.0, Δv₂=1.2), 2.89(2H) cyclohexane72-74 CHNote ¹lit. value = 71-73° C. (J. Chem. Res. Miniprint, 1981, 4,1043-1056).Note ²nd = not determined; insufficient resolution.Note ³lit. value = δ 3.08(v.s.).Part III: Preparation of Intermediates of Table 6.3:

Preparative Example 17043 Preparation of Intermediate of Formula 170431-(4-Pyridylmethyl)Cyclohexyl Isocyanate

A mixture of 0.5 g of the carboxylic acid 17035 described above, 0.5 mLdiphenylphosphoryl azide, and 25 mL toluene was heated at 110° C. for0.75 hr. The cooled mixture was placed on a column of silica gel andrapidly eluted with EtOAc-hexane (2:3) to afford 0.39 g of the titlecompound as an oil, which was used soon after preparation. The product17043 was stored in 1 M CH₂Cl₂ solution for brief periods. H¹-NMR(CDCL₃) δ 8.3 (br s, 2H), 7.17 (d, J=5.4, 2H), 2.78 (s, 2H), 1.8-1.1 (m,10H).

General Example Table 6.3 1-(Heteroarylmethyl)Cyclohexyl Isocyanates

The procedure of the preceding example 17043 was applied to the acids ofTable 6.2 to obtain the isocyanates 17048, 17049, 17050, 17051, 17052,17053 and 17054 shown in Table 6.3. TABLE 6.3 chroma- StartingIsocyanate Yield tography acid Product % solvent 17036

17048 75 EtOAc- hexane(2:3) 17037

17049 82 EtOAc- hexane(2:3) 17038

17050 68 Et₂O- hexane(1:9) 17039

17051 29 not chroma- tographed 17040

17052 21 Et₂O- hexane(1:9) 17041

17053 78 Et₂O- hexane(1:9) 17042

17054 74 Et₂O- hexane(1:9)

HCV inhibitors 4921, 4922, 4923, 4927, 4933, 4938, 4939, 4940, 4941,4944, 4946, 4947, 4955, 4962, 4965, 4966 of Table 6 were prepared usingisocyanates 17043, 17048, 17049, 17050, 17051, 17052, 17053 and 17054shown in table 6.3 according the general procedure described before.

Example XX Preparation of General Intermediates 4948.01 Used in thePreparation of HCV Inhibitor 4948, 49494972, 4973 of Table 6 Accordingthe General Procedure Describe Before

Step 1

Step 1: Compound 4948.02 (2.5 g, 10 mmol) was taken in dioxane (30 mL).Lawesson's reagent (2.23 g, 5.5 mmol, STENCH) was added and the reactionmixture was heated at 60° C. for 2 hrs under nitrogen atmosphere. Thereaction mixture was allowed to cool to room temperature over 3.5 hrperiod, while stirring. The reaction mixture was then concentrated.Saturated sodium bicarbonate solution (50 mL) was added to the residueand extracted with chloroform (2×). The combined chloroform layer wasconcentrated to afford 2.8 g of 4948.03 which was used without anypurification.

Step 2: Preparation of bromoacetaldehyde: Bromoacetaldehydediethylacetal (2 mL) was added to concentrated HCl (2.4 mL) and heatedat 60° C. for 30 min. This mixture was then cooled to 10° C. DMF (30 mL)was added followed by powdered molecular sieves (one spatula). Thesolution was decanted and used immediately as described below.

A solution of bromoacetaldehyde in DMF prepared as above was added to4948.03 (1.4 g, from Step 1) and heated at 60° C. for 5 hrs. At thistime the reaction mixture was cooled to room temperature, diluted withethyl acetate (50 mL) and washed with saturated sodium bicarbonate (100mL). The organic layer was separated and the aqueous layer was furtherextracted with ethyl acetate (50 mL). The combined organic layer waswashed with water (100 mL), brine (100 mL), dried (Na₂SO₄) andconcentrated. The residue was purified by flash chromatography using12/88 EtOAc/hexanes which afforded 964 mg of intermediate that was takenup in 33% hydrogen bromide in acetic acid (10 mL). This mixture wasstirred at room temperature for 1 hr. Diethyl ether (100 mL) was addedwhich resulted in a white precipitate. Filtration followed by washingwith diethyl ether (2×) provided 4948.01 as a white solid inquantitative yield.

Example XXI Preparation of General Intermediates 4925.01 Used in thePreparation of HCV Inhibitor 4925, 4926, 4928, 4929, 4952, 4959, 4968 ofTable 6 According the General Procedure Describe Before

Step 1

To a solution of methylcyclohexanecarboxylate 4925.03 (2.54 mL, 17.68mmol) in THF (100 mL) at −78° C. was added LDA (2.0M inhexanes/THF/ethylbenzene, 17.68 mL, 35.36 mmol) under nitrogenatmosphere. The reaction mixture was maintained at that temperature for30 min. Then a solution of the aldehyde 4925.02 (2.0 g, 17.68 mmol) inTHF (10 mL) was added dropwise. The temperature was slowly brought to10° C. over 1.5 hr. TLC indicated complete consumption of startingmaterials. The reaction was quenched with saturated ammonium chloridesolution/brine (200 mL) and extracted with diethyl ether (2×). Thecombined ether layer was dried (Na₂SO₄) and concentrated. Purificationof the residue by flash chromatography using 23/77 EtOAc/hexanesafforded 2.72 g of the required material, 4925.04.Step 2

To a solution of 4925.04 (1.02 g, 4.0 mmol) in THF (30 mL) was addedthiocarbonyl diimidazole (1.78 g, 10.0 mmol). The mixture was refluxedunder nitrogen atmosphere for 5 hrs. The reaction mixture was cooled toroom temperature, diluted with diethyl ether, washed with saturatedammonium chloride solution, dried (Na₂SO₄) and concentrated.Purification of the residue by flash chromatography using 20/80 to 30/70EtOAc/dichloromethane afforded 1.3 g of the required material, 4925.05.Step 3

Compound 4925.05 (1.27 g, 3.48 mmol) was taken in toluene (40 mL). Tothis were added AIBN (2,2′-Azobisisobutyronitrile, 57 mg, 0.348 mmol)and TBTH (tri-n-butyl tin hydride, 1.87 mL, 6.96 mmol) under nitrogenatmosphere. The mixture was refluxed overnight (16 hrs). At this timethe reaction mixture was cooled to room temperature, and quenched withaqueous 1N HCl (100 mL). It was then extracted with diethyl ether (100mL). The organic layer was washed with 1N HCl (100 mL), dried (Na₂SO₄)and concentrated. Purification of the residue by flash chromatographyusing 8/92 EtOAc/dichloromethane afforded 400 mg of the requiredmaterial, 4925.05.Step 4

To a mixture of compound 4925.05 (478 mg, 2.0 mmol) in dioxane (5 mL)and water (5 mL) was added solid potassium hydroxide (336 mg, 6 mmol).The reaction mixture was heated at 80° C. for 2 hrs and 100° C. for 3hrs. The reaction mixture was cooled to room temperature, concentratedand quenched with aqueous 1N HCl. The aqueous layer was extracted withdichloromethane, dried (Na₂SO₄) and concentrated to afford 390 mg of therequired material, 4925.06 LC-MS: 226 (M+H).Step 5

The acid 4925.06 (390 mg, 1.73 mmol) was taken in toluene (10 mL).Triethylamine (0.27 mL, 1.9 mmol) and DPPA (Diphenylphosphoryl azide,0.42 mL, 1.94 mmol) were then added. The reaction mixture was refluxedfor 5 hrs and cooled to room temperature. This resulted in the formationof the isocyanate 4925.01 which was used further as a 0.173 M solutionin toluene.

Example XXII Preparation of Isocyanate 4953.01 Used in the Preparationof HCV Inhibitor 4953 of Table 6

Step 1

PhMgBr (2.5 equiv, 40 mL) was added @ −78° C. to a Et2O (200 mL)solution of commercially available Weinreb amide (Aldrich Chemical Co.,Milwaukee, Wis., USA, 12 g, 46 mmol). After 2 h, reaction was quenchedby addition of HCl 1.0 N, diluted with EtOAc and washed with brine,dried over MgSO₄, filtered and concentrated under vacuo. The residue waspurified by HPFC Biotage 75+S, Seg1: 2% B to 2% B, Linear, 320 mL/Seg2:2% B to 8% B, Linear, 3200 mL/Seg3: Hold 8% for 5CV(1600 mL). 3.76 g of4953.02 were obtained.Step 2

To a 0° C. solution of 4953.02 (1.5 g, 5.4 mmol) in MeOH (100 mL) wasadded NaBH4 (5 equiv, 27 mmol, 1.02 g). Reaction was warmed-up to RT andstirred until thin layer chromatography indicated complete consumptionof the starting material (˜0.5 hr). Reaction was stopped by addition ofHCl 1.0 N and extracted with EtOAc. Organic layer was dried over MgSO4,filtered and concentrated under vacuo. The residue was purified by HPFCBiotage 25+S, Seg1: 3% B, Linear, 120 mL/Seg2: 3% B to 12% B, Linear,1200 mL/Seg3: Hold10% for 240 mL. Purification furnished 1.35 g of4953.03.Step 3

To a solution of N2 flushed solution of 4953.03 (1.35 g, 4.8 mmol) inMeOH (50 ml) was added 10% Pd/C catalyst (0.5 g). The resultingsuspension was hydrogenated for 18 h. The catalyst was removed byfiltration through a pad of celite and washed with EtOAc. The combinedfiltrate and washings were evaporated under vacuum to dryness to provideafter purification the desired product 4418 (85 mg) and recovered4953.04.Step 4

4953.04 (28 mg, 0.10 mmol) was treated with 4.0 N HCl solution inDioxane described previously to deliver quantitatively 4953.05.Step5

4953.05 (28 mg, 0.10 mmol) was treated with phosgene as describedpreviously to deliver 4953.01 that was used as described before toprepare HCV inhibitor 4953 of Table 6.

Example XXIII Preparation of Isocyanate 4950.01 Used in the Preparationof HCV Inhibitor 4950 of Table 6

Step 1

To a −25° C. solution of ketone 4953.02 prepared in step 1 ofpreparative example XXII (2.77 g, 10 mmol) in THF (50 mL) was addedTMSCH₂MgCl (1.0M in Et2O, 2 equiv, 20 mmol, 20 mL). The temperature wasslowly raised to 0° C. and stirred for 1 h, quenched with H2O (5 mL) anddiluted with EtOAc. The reaction mixture was washed with NH4Cl sat andbrine. Organic layer was dried over MgSO4, filtered and concentratedunder vacuo. To a 0° C. solution of the above crude in THF (50 mL) wasadded KHMDS (2.7 equiv, 0.5M in PhMe, mmol, 54 mL). The mixture wasstirred at 0° C. for 1.5 h then RT for 3 hr then quenched with saturatedNH4Cl and diluted with EtOAc. The organic layer was washed with brine,dried over MgSO4, filtered and concentrated under vacuo. purificationvia HPFC, 40+S, Seg1: Hold 2% B, Linear, 60 mL/Seg2: 2% B to 8% B,Linear, 600 mL/Seg3: Hold 8% B, Linear, 300 mL. 0.5 g of 4950.02 wereisolated.Step 2

To a rt solution of 4950.02 (100 mg, 0.36 mmol) in DCM 3 mL was added 1mL of TFA. Reaction turned yellow immediately. After 10 min, TLC showedno starting material and reaction was diluted with Hexanes andconcentrated to dryness. The resulting yellow oil was placed under highvacuum overnight and analyzed by NMR. 109 mg of 4950.03 were obtained.Step 3

A DCM (5 mL) solution of TFA salt 4950.03 (109 mg, 0.36 mmol) was addedto a 0° C. solution of saturated aqueous NaHCO3 (5 mL) and Phosgene (2equiv, 0.72 mmol, 0.36 mL). Rapid stirring was set immediately and theice-cooled reaction mixture was stirred for 2 hours at high speed. After2 hours, the organic phase (lower) was separated and was then dried overanhydrous MgSO4 and concentrated to half volume under vacuum withcooling bath. Dilute to 3.6 mL (0.1 M solution in DCM of 4950.01) thatwas used as described before to prepare HCV inhibitor 4950 of Table 6.

Example XXIV Preparation of Isocyanate 4942.01 Used in the Preparationof HCV Inhibitor 4942 of Table 6

Step 1

To a 0° C. solution of DAST (2 equiv, 40 mL) in DCM (290 mL) was added asolution 4-cyclohexanone carboxylic Acid Ethyl Ester 4942.02 (25 g, 147mmol) in DCM (100 mL) dropwise over 20 min. the mixture was allowed tostir at RT overnight. H2O (50 ml) was then added carefully (CAUTION:STRONG EXOTHERM). The mixture was basified to PH 5 (takes a great amountof time, watch out for violent acid-base reaction) with saturatedNaHCO3. Finally, aqueous layer was removed by extraction and organiclayer was washed with saturated NaHCO3 without any problem. Aqueouslayer was back extracted with EtOAc and both combined organic layerswere dried over MgSO4, filtered and the solvent removed by evaporationunder reduced pressure to yield crude 4942.03 (29.33 g) as a dark redoil.Step 2

To a −78° C. solution of ethyl ester 4942.03 (20 mmol, 3.84 g) in THF(25 mL) was added 1.0 equiv of LDA (10 mL). Addition of LDA produced alight yellow color. After 15 min, Benzyl bromide (1.1 equiv, 22 mmol,2.61 mL) was added dropwise. Reaction color turned gold immediately.Reaction was then gradually warmed-up to rt overnight. Reaction wasstopped by addition of Sat. aqueous NH4Cl. Reaction was diluted withEtOAc and layers were separated. Washed with NaHCO3, then brine. Organiclayer was dried over MgSO4, filtered and concentrated under vacuo.Purification via HPFC, 40+S, Seg1: Hold 5% B, Linear, 60 mL/Seg2: 5% Bto 20% B, Linear, 600 mL/Seg3: Hold 20% B, Linear, 300 mL. 0.915 g of4942.04 was isolated.Step 3

To a solution of 4942.04 (0.8 g, 2.8 mmol) in EtOH/H2O (36 mL/4 mL) wasadded KOH (10 equiv, 28 mmol, 1.57 g). The reaction was brought toreflux until completion. 48 h reflux was necessary to observecompletion. Diluted with Et2O and basified to Ph=9 with saturatedNaHCO3. Et2O layer was discarded to remove non carboxylic acid material.Aqueous layer was acidified to Ph=1 with HCl 1.0N and extracted withEtOAc. The organic layer was washed with brine, dried over MgSO4,filtered and concentrated under vacuo. 535 mg of a light orange solidwere isolated as 4942.05.Step 4

Acid 4942.05 (335 mg, 1.314 mmol) in Toluene (10 mL) was treated asdescribed previously to afford isocyanate 4942.01 that was used asdescribed before to prepare HCV inhibitor 4942 of Table 6.

Example XXV Preparation of Isocyanate 4954.01 Used in the Preparation ofHCV Inhibitor 4954 of Table 6

To a solution of 50.2 mg of compound 4954.02 (Adam, Waldemar; Baeza,Jaime; Liu, Ju-Chao, Journal of the American Chemical Society (1972),94(6), 2000-6) in toluene (4.0 mL) was added DPPA (0.06 mL) and Et₃N(0.037 mL). The reaction mixture was heated at 110° C. for 40 min,cooled and washed with Satd. NaHCO₃, dried over MgSO₄, filtered andconcentrated to afford isocyanate 4954.01. The crude obtained was usedwithout purification to prepare as described before HCV inhibitor 4954of Table 6. TABLE 6 cmpd Ki* # MW range 4921

623 A 4922

628 A 4923

628 A 4925

629 A 4926

643 A 4927

649 A 4928

670 A 4929

684 A 4930

660 A 4931

658 A 4933

649 A 4934

664 A 4935

690 A 4936

620 A 4937

664 A 4938

654 A 4939

637 A 4940

654 A 4941

649 A 4942

658 A 4943

652 A 4944

623 A 4945

652 A 4946

661 A 4947

665 A 4948

617 A 4949

603 A 4950

608 A 4951

640 A 4952

711 A 4953

596 A 4954

596 A 4955

649 A 4956

636 A 4957

648 A 4958

698 A 4959

657 A 4960

636 A 4962

625 B 4964

610 B 4965

621 B 4966

611 B 4967

834 B 4968

669 B 4969

638 B 4970

726 B 4971

690 B 4972

645 B 4973

631 B 4974

742 B 4975

679 B 4976

694 B 4977

754 B 4978

723 B 4979

665 B 4980

702 B 4981

652 B 4982

754 B 4983

788 B

The present invention relates to novel HCV protease inhibitors. Thisutility can be manifested in their ability to inhibit the HCV NS2/NS4aserine protease. A general procedure for such demonstration isillustrated by the following in vitro assay.

Assay for HCV Protease Inhibitory Activity:

Spectrophotometric Assay: Spectrophotometric assay for the HCV serineprotease can be performed on the inventive compounds by following theprocedure described by R. Zhang et al, Analytical Biochemistry, 270(1999) 268-275, the disclosure of which is incorporated herein byreference. The assay based on the proteolysis of chromogenic estersubstrates is suitable for the continuous monitoring of HCV NS3 proteaseactivity. The substrates are derived from the P side of the NS5A-NS5Bjunction sequence (Ac-DTEDVVX(Nva), where X=A or P) whose C-terminalcarboxyl groups are esterified with one of four different chromophoricalcohols (3- or 4-nitrophenol, 7-hydroxy-4-methyl-coumarin, or4-phenylazophenol). Illustrated below are the synthesis,characterization and application of these novel spectrophotometric estersubstrates to high throughput screening and detailed kinetic evaluationof HCV NS3 protease inhibitors.

Materials and Methods:

Materials: Chemical reagents for assay related buffers are obtained fromSigma Chemical Company (St. Louis, Mo.). Reagents for peptide synthesiswere from Aldrich Chemicals, Novabiochem (San Diego, Calif.), AppliedBiosystems (Foster City, Calif.) and Perseptive Biosystems (Framingham,Mass.). Peptides are synthesized manually or on an automated ABI model431A synthesizer (from Applied Biosystems). UVNIS Spectrometer modelLAMBDA 12 was from Perkin Elmer (Norwalk, Conn.) and 96-well UV plateswere obtained from Corning (Corning, N.Y.). The prewarming block can befrom USA Scientific (Ocala, Fla.) and the 96-well plate vortexer is fromLabline Instruments (Melrose Park, Ill.). A Spectramax Plus microtiterplate reader with monochrometer is obtained from Molecular Devices(Sunnyvale, Calif.).

Enzyme Preparation: Recombinant heterodimeric HCV NS3/NS4A protease(strain 1a) is prepared by using the procedures published previously (D.L. Sali et al, Biochemistry, 37 (1998) 3392-3401). Proteinconcentrations are determined by the Biorad dye method using recombinantHCV protease standards previously quantified by amino acid analysis.Prior to assay initiation, the enzyme storage buffer (50 mM sodiumphosphate pH 8.0, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside and10 mM DTT) is exchanged for the assay buffer (25 mM MOPS pH 6.5, 300 mMNaCl, 10% glycerol, 0.05% lauryl maltoside, 5 μM EDTA and 5 μM DTT)utilizing a Biorad Bio-Spin P-6 prepacked column.

Substrate Synthesis and Purification: The synthesis of the substrates isdone as reported by R. Zhang et al, (ibid.) and is initiated byanchoring Fmoc-Nva-OH to 2-chlorotrityl chloride resin using a standardprotocol (K. Barlos et al, Int. J. Pept. Protein Res., 37 (1991),513-520). The peptides are subsequently assembled, using Fmoc chemistry,either manually or on an automatic ABI model 431 peptide synthesizer.The N-acetylated and fully protected peptide fragments are cleaved fromthe resin either by 10% acetic acid (HOAc) and 10% trifluoroethanol(TFE) in dichloromethane (DCM) for 30 min, or by 2% trifluoroacetic acid(TFA) in DCM for 10 min. The combined filtrate and DCM wash isevaporated azeotropically (or repeatedly extracted by aqueous Na₂CO₃solution) to remove the acid used in cleavage. The DCM phase is driedover Na₂SO₄ and evaporated.

The ester substrates are assembled using standard acid-alcohol couplingprocedures (K. Holmber et al, Acta Chem. Scand., B33 (1979) 410-412).Peptide fragments are dissolved in anhydrous pyridine (30-60 mg/ml) towhich 10 molar equivalents of chromophore and a catalytic amount (0.1eq.) of para-toluenesulfonic acid (pTSA) were added.Dicyclohexylcarbodiimide (DCC, 3 eq.) is added to initiate the couplingreactions. Product formation is monitored by HPLC and can be found to becomplete following 12-72 hour reaction at room temperature. Pyridinesolvent is evaporated under vacuum and further removed by azeotropicevaporation with toluene. The peptide ester is deprotected with 95% TFAin DCM for two hours and extracted three times with anhydrous ethylether to remove excess chromophore. The deprotected substrate ispurified by reversed phase HPLC on a C3 or C8 column with a 30% to 60%acetonitrile gradient (using six column volumes). The overall yieldfollowing HPLC purification can be approximately 20-30%. The molecularmass can be confirmed by electrospray ionization mass spectroscopy. Thesubstrates are stored in dry powder form under desiccation.

Spectra of Substrates and Products: Spectra of substrates and thecorresponding chromophore products are obtained in the pH 6.5 assaybuffer. Extinction coefficients are determined at the optimal off-peakwavelength in 1-cm cuvettes (340 nm for 3-Np and HMC, 370 nm for PAP and400 nm for 4-Np) using multiple dilutions. The optimal off-peakwavelength is defined as that wavelength yielding the maximum fractionaldifference in absorbance between substrate and product (productOD—substrate OD)/substrate OD).

Protease Assay: HCV protease assays are performed at 30° C. using a 200μl reaction mix in a 96-well microtiter plate. Assay buffer conditions(25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5μM EDTA and 5 μM DTT) are optimized for the NS3/NS4A heterodimer (D. L.Sali et al, ibid.)). Typically, 150 μl mixtures of buffer, substrate andinhibitor are placed in wells (final concentration of DMSO≦4% v/v) andallowed to preincubate at 30° C. for approximately 3 minutes. Fifty μlsof prewarmed protease (12 nM, 30° C.) in assay buffer, is then used toinitiate the reaction (final volume 200 μl). The plates are monitoredover the length of the assay (60 minutes) for change in absorbance atthe appropriate wavelength (340 nm for 3-Np and HMC, 370 nm for PAP, and400 nm for 4-Np) using a Spectromax Plus microtiter plate readerequipped with a monochrometer (acceptable results can be obtained withplate readers that utilize cutoff filters). Proteolytic cleavage of theester linkage between the Nva and the chromophore is monitored at theappropriate wavelength against a no enzyme blank as a control fornon-enzymatic hydrolysis. The evaluation of substrate kinetic parametersis performed over a 30-fold substrate concentration range (˜6-200 μM).Initial velocities are determined using linear regression and kineticconstants are obtained by fitting the data to the Michaelis-Mentenequation using non-linear regression analysis (Mac Curve Fit 1.1, K.Raner). Turnover numbers (k_(cat)) are calculated assuming the enzyme isfully active.

Evaluation of Inhibitors and Inactivators: The inhibition constants(K_(i)) for the competitive inhibitors Ac-D-(D-Gla)-L-I-(Cha)-C-OH (27),Ac-DTEDVVA(Nva)-OH and Ac-DTEDVVP(Nva)-OH are determined experimentallyat fixed concentrations of enzyme and substrate by plotting v_(o)/v_(i)vs. inhibitor concentration ([I]_(o)) according to the rearrangedMichaelis-Menten equation for competitive inhibition kinetics:v_(o)/v_(i)=1+[I]_(o)/(K_(i)(1+[S]_(o)/K_(m))), where v_(o) is theuninhibited initial velocity, v_(i) is the initial velocity in thepresence of inhibitor at any given inhibitor concentration ([I]_(o)) and[S]_(o) is the substrate concentration used. The resulting data arefitted using linear regression and the resulting slope,1/(K_(i)(1+[S]_(o)/K_(m)), is used to calculate the K_(i) value. The Ki*values of some of the inventive compounds are shown in Table 8: TABLE 8Ki* structure (nM)

5

8

15

13

22

30

40

14

13

7

9

30

13

51

17

5

10

4.3

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

1. A compound, or enantiomers, stereoisomers, rotamers, tautomers,diastereomers and racemates of said compound, or a pharmaceuticallyacceptable salt, solvate or ester of said compound, said compound havingthe general structure shown in Formula I:

wherein: R¹ is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹ and R¹⁰ can bethe same or different, each being independently selected from the groupconsisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, heteroaryl-,cycloalkyl-, heterocyclyl-, arylalkyl-, and heteroarylalkyl; or R¹⁰ isR¹⁴ wherein R14 is H, alkyl, aryl, heteroaryl, cycloalkyl, alkyl-aryl,alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaryl-alkyl; Aand M can be the same or different, each being independently selectedfrom R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected toeach other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC(R); L is C(H), C(R), CH₂C(R), or C(R)CH₂; R, R′, R², and R³ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heterocyclyl-,aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-,aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in NRR′ areconnected to each other such that NRR′ forms a four to eight-memberedheterocyclyl; and Y is selected from the following moieties:

wherein G is NH; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same or different,each being independently selected from the group consisting of H, alkyl,alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, oralternately, R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered cycloalkyl, heteroaryl or heterocyclyl structure, andlikewise, independently R¹⁷ and R¹⁸ are connected to each other to forma three to eight-membered cycloalkyl or heterocyclyl; wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.
 2. The compound of claim 1, whereinR₁ is NR⁹R¹⁰, and R⁹ is H, R¹⁰ is H, or R¹⁴ wherein R¹⁴ is H, alkyl,aryl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl,alkenyl, alkynyl or heteroaryl-alkyl.
 3. The compound of claim 2,wherein R¹⁴ is selected from the group consisting of:


4. The compound of claim 1, wherein R² is selected from the groupconsisting of the following moieties:


5. The compound of claim 1, wherein R³ is selected from the groupconsisting of:

wherein R³¹ is OH or O-alkyl; and R³² is H, C(O)CH₃, C(O)OtBu orC(O)N(H)tBu.
 6. The compound of claim 1, wherein R³ is selected from thegroup consisting of the following moieties:


7. The compound of claim 1, wherein Y is selected from the followingmoieties:

wherein G is NH; and R¹⁵, R¹⁶ R¹⁷ and R¹⁸ are as defined in claim
 1. 8.The compound of claim 7, wherein Y is selected from the group consistingof:

wherein Y³¹ is selected from the group consisting of:

Y³² is selected from the group consisting of:

and Y¹² is selected from the group consisting of H, CO₂H, CO₂Me, OMe, F,Cl, Br, NH₂, N(H)S(O₂)CH₃, N(H)C(O)CH₃, NO₂, NMe₂, S(O₂)NH₂, CF₃, Me,OH, OCF₃, and C(O)NH₂ and Y³³ is selected from the group consisting of:


9. The compound of claim 1, wherein the moiety:

is selected from the following structures:


10. The compound of claim 9, wherein the moiety:

is selected from the following structures:


11. The compound of claim 10, wherein the moiety:

is selected from the following structures:


12. The compound of claim 1, R¹ is NHR¹⁴, where R¹⁴ is selected from thegroup consisting of:

R² is selected from the group consisting of the following moieties:

R³ is selected from the group consisting of the following moieties:

Y is selected from the group consisting of:

wherein Y³¹ is selected from the group consisting of:

Y³² is selected from the group consisting of:

and Y¹² is selected from the group consisting of H, CO₂H, CO₂Me, OMe, F,Cl, Br, NH₂, N(H)S(O₂)CH₃, N(H)C(O)CH₃, NO₂, NMe₂, S(O₂)NH₂, CF₃, Me,OH, OCF₃, and C(O)NH₂ and Y³³ is selected from the group consisting of:

and the moiety:


13. A pharmaceutical composition comprising as an active ingredient atleast one compound of claim
 1. 14. The pharmaceutical composition ofclaim 13 for use in treating an infection of HCV.
 15. The pharmaceuticalcomposition of claim 14 additionally comprising at least onepharmaceutically acceptable carrier.
 16. The pharmaceutical compositionof claim 15, additionally containing at least one antiviral agent. 17.The pharmaceutical composition of claim 16, additionally containing atleast one interferon.
 18. The pharmaceutical composition of claim 17,wherein said at least one antiviral agent is ribavirin and said at leastone interferon is a-interferon or pegylated interferon.
 19. A method oftreating an infection of HCV, said method comprising administering to apatient in need of such treatment a pharmaceutical composition whichcomprises therapeutically effective amounts of at least one compound ofclaim
 1. 20. The method of claim 19, wherein said administration is oralor subcutaneous.
 21. The use of a compound of claim 1 for themanufacture of a medicament to treat disorders associated with the HCV.22. A method of preparing a pharmaceutical composition for treating thedisorders associated with the HCV, said method comprising bringing intointimate physical contact at least one compound of claim 1 and at leastone pharmaceutically acceptable carrier.
 23. A compound exhibiting HCVprotease inhibitory activity, or enantiomers, stereoisomers, rotamers,tautomers, diastereomers and racemates of said compound, or apharmaceutically acceptable salt, solvate or ester of said compound,said compound being selected from the compounds of structures listedbelow:


24. A pharmaceutical composition for treating an infection of HCV, saidcomposition comprising therapeutically effective amount of one or morecompounds in claim 23 and a pharmaceutically acceptable carrier.
 25. Thepharmaceutical composition of claim 24, additionally containing at leastone antiviral agent.
 26. The pharmaceutical composition of claim 25,additionally containing at least one interferon or PEG-interferon alphaconjugate.
 27. The pharmaceutical composition of claim 26, wherein saidat least one antiviral agent is ribavirin and said at least oneinterferon is α-interferon or pegylated interferon.
 28. A method oftreatment of an infection of hepatitis C virus, comprising administeringan effective amount of one or more compounds of claim
 23. 29. A methodof modulating the activity of hepatitis C virus (HCV) protease,comprising contacting HCV protease with one or more compounds of claim23.
 30. A method of treating, preventing, or ameliorating one or moresymptoms of hepatitis C, comprising administering a therapeuticallyeffective amount of one or more compounds of claim
 23. 31. The method ofclaim 30, wherein the HCV protease is the NS3/NS4a protease.
 32. Themethod of claim 31, wherein the compound or compounds inhibit HCVNS3/NS4a protease.
 33. A method of modulating the processing ofhepatitis C virus (HCV) polypeptide, comprising contacting a compositioncontaining the HCV polypeptide under conditions in which saidpolypeptide is processed with one or more compounds of claim
 23. 34. Amethod of treating an infection of HCV, said method comprisingadministering to a patient in need of such treatment, a pharmaceuticalcomposition which comprises therapeutically effective amounts of atleast one compound, or enantiomers, stereoisomers, rotamers, tautomers,diastereomers and racemates of said compound, or a pharmaceuticallyacceptable salt, solvate or ester of said compound, said compound beingselected from the compounds of claim
 23. 35. A compound of claim 1 inpurified form.